NK1 antagonists

ABSTRACT

A NK 1  antagonist having the formula (I), 
                         
wherein Ar 1  and Ar 2  are optionally substituted phenyl or heteroaryl, X 1  is an ether, thio or imino linkage, R 4  and R 5  are not both H or alkyl, and the remaining variables are as defined in the specification, useful for treating a number of disorders, including emesis, depression, anxiety and cough. Pharmaceutical compositions. Methods of treatment and combinations with other agents are also disclosed.

RELATED APPLICATIONS

This application is a divisional of application U.S. application Ser.No. 10/321,687, filed Dec. 17, 2002, now allowed and herein incorporatedby reference, which in turn claims the benefit under 35 USC 119(e) toprovisional application U.S. application Ser. No. 60/341,452, filed Dec.18, 2001.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application60/341,452, filed Dec. 18, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to an antagonist of the neuropeptide neurokinin-1(NK₁ or NK-1) receptor.

2. Description of Related Art

Tachykinins are peptide ligands for neurokinin receptors. Neurokininreceptors, such as NK₁, NK₂ and NK₃, are involved in a variety ofbiological processes. They can be found in a mammal's nervous andcirculatory systems, as well as in peripheral tissues. Consequently, themodulation of these types of receptors have been studied to potentiallytreat or prevent various mammalian disease states. For instance, NK₁receptors have been reported to be involved in microvascular leakage andmucus secretion. Representative types of neurokinin receptor antagonistsand their uses can be found in: U.S. Pat. No. 5,760,018 (1998) (pain,inflammation, migraine and emesis), U.S. Pat. No. 5,620,989 (1997)(pain, nociception and inflammation), WO 95/19344 (1995) (same), WO94/13639 (1994) (same) and WO 94/10165 (1994) (same). Further types ofNK₁ receptor antagonists can be found in Wu et al, Tetrahedron 56,3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399(2001); and Rogiers et al, Tetrahedron 57, 8971-8981 (2001).

It would be beneficial to provide a NK₁ antagonist that is potent,selective, and possesses beneficial therapeutic and pharmacologicalproperties, and good metabolic stability. It would further be beneficialto provide a NK₁ antagonist that is effective for treating a variety ofphysiological disorders, symptoms and diseases while minimizing sideeffects. The invention seeks to provide these and other benefits, whichwill become apparent as the description progresses.

SUMMARY OF THE INVENTION

In one aspect of the invention, a compound is provided having theformula (I):

or a pharmaceutically-acceptable salt thereof, wherein

Ar¹ and Ar² are each independently selected from the group consisting ofR¹⁷-heteroaryl and

X¹ is —O—, —S—, —SO—, —SO₂—, —NR³⁴—, —N(COR¹²)— or —N(SO₂R¹⁵)—;

when X¹ is —SO—, —SO₂—, —N(COR¹²)— or —N(SO₂R¹⁵)—, then:

-   -   R¹ and R² are each independently selected from the group        consisting of H, C₁-C₆ alkyl, hydroxy(C₁-C₃alkyl), C₃-C₈        cycloalkyl, —CH₂F, —CHF₂ and —CF₃; or R¹ and R², together with        the carbon atom to which they are both attached, form a        chemically feasible C₃ to C₆ alkylene ring; or

when X¹ is —O—, —S— or —NR³⁴—, then:

-   -   R¹ and R² are each independently selected from the group        consisting of H, C₁-C₆ alkyl, hydroxy(C₁-C₃alkyl), C₃-C₈        cycloalkyl, —CH₂F, —CHF₂ and —CF₃; or R¹ and R², together with        the carbon atom to which they are both attached, form a        chemically feasible C₃ to C₆ alkylene ring; or R¹ and R²,        together with one another and the carbon atom to which they are        both attached, form a C═O group;

R³ is selected from the group consisting of H, C₁-C₆ alkyl,hydroxy(C₁-C₃ alkyl), C₃-C₈ cycloalkyl, —CH₂F, —CHF₂ and —CF₃;

each R⁶ is independently selected from the group consisting of H, C₁-C₆alkyl and —OH;

each R⁷is independently selected from the group consisting of H andC₁-C₆ alkyl;

n₂ is 1 to 4;

R⁴ and R⁵ are each independently selected from the group consisting of—(CR²⁸R²⁹)_(n1)-G,

where,

-   -   n₁ is 0 to 5; and    -   G is H, —CF₃, —CHF₂, —CH₂F, —OH, —O—(C₁-C₆ alkyl), —OCH₂F,        —OCHF₂, —OCF₃, —OCH₂CF₃, —O—(C₃-C₈ cycloalkyl),        —O—(C₁-C₆)alkyl(C₃-C₈ cycloalkyl), —NR¹³R¹⁴, —SO₂NR¹³R¹⁴,        —NR¹²SO₂R¹³, —NR¹²C(O)R¹⁴, —NR¹²C(O)O¹³, —NR¹²(C(O)NR¹³R¹⁴),        —C(O)NR¹³R¹⁴, —C(O)OR¹³, —C₃-C₈ cycloalkyl, (R¹⁹)_(r)-aryl,        (R¹⁹)r-heteroaryl, —OC(O)R¹⁴, —OC(O)NR¹³R¹⁴, —C(═NOR¹⁴)(R¹³),        —C(O)R¹³, —C(OR¹²)(R¹³)(R¹⁴), heterocycloalkenyl optionally        substituted by 1 to 4 substituents independently selected from        the group consisting of R³⁰ and R³¹,

R⁴ and R⁵ together are ═O, ═NOR¹²; or

R⁴ and R⁵, together with the carbon atom to which they are bothattached, form a chemically feasible 4- to 8-membered heterocycloalkylor heterocycloalkenyl ring containing 1 to 3 groups independentlyselected from X², provided that at least one X² is —NR³⁵—, —O—, —S—,—S(O)— or —SO₂—, the chemically feasible ring being optionallysubstituted with from 1 to 6 substituents independently selected fromthe group consisting of R³⁰ and R³¹;

provided that R⁴ and R⁵ are not both selected from the group consistingof H, alkyl and cycloalkyl;

further provided that, when one of R⁴ and R⁵ is —OH, then the other oneof R⁴ and R⁵ is not alkyl or (R¹⁹)_(r)-aryl;

R⁸, R⁹ and R¹⁰ are each independently selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, —OR¹², halogen, —CN, —NO₂, —CF₃,—CHF₂, —CH₂F, —CH₂CF₃, —OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —COOR¹²,—CONR²¹R²², —OC(O)NR²¹R²², —OC(O)R¹², —NR²¹COR¹², —NR²¹CO₂R¹⁵,—NR²¹CONR²¹R²², —NR²¹ SO₂R¹⁵, —NR²¹R²², —SO₂NR²¹R²², —S(O)_(n6)R¹⁵,(R¹⁹)_(r)-aryl and (R¹⁹)_(r)-heteroaryl:

R¹² is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;

R¹³ and R¹⁴ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,—CH₂CF₃, aryl and heteroaryl; or

R¹³ and R¹⁴, together with the nitrogen atom to which they are bothattached, form a chemically feasible 4- to 7-membered saturated orunsaturated ring that is optionally substituted with —OR¹², where one ofthe carbon atoms in the ring is optionally replaced by a heteroatomselected from the group consisting of —O—, —S— and —NR³⁴;

n₆ is 0, 1 or 2;

R¹⁵ is C₁-C₆ alkyl, C₃-C8 cycloalkyl, —CF₃ or —CH₂CF₃;

R¹⁸ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,hydroxy(C₂-C₆)alkyl or —P(O)(OH)₂;

each R¹⁹ is a substituent on the aryl or heteroaryl ring to which it isattached, and is independently selected from the group consisting of H,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆ alkoxy, —OH, halogen, —CN, —NO₂,—CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —O—(C₁-C₆ alkyl), —O—(C₃-C₈cycloalkyl), —COOR¹², —CONR²¹R²², —OC(O)NR²¹R²², —OC(O)R¹², —NR²¹R²²,—NR²¹COR¹², —NR²¹CO₂R¹², —NR²¹CONR²¹R²², —NR²¹SO₂R¹⁵ and —S(O)_(n6)R¹⁵;

R²¹ and R²² are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl and benzyl; or

R²¹ and R²², together with the nitrogen atom to which they are bothattached, form a chemically feasible 4- to 7-membered saturated orunsaturated ring, where one of the carbon atoms in the ring isoptionally replaced by a heteroatom selected from the group consistingof —O—, —S— and —NR³⁴—;

R²³ and R²⁴ are each independently selected from the group consisting ofH and C₁-C₆ alkyl; or

R²³ and R²⁴, together with the carbon atom to which they are bothattached, form a C═O or cyclopropyl group;

R²⁷ is H, —OH or C₁-C₆ alkyl;

R²⁸ and R²⁹ are each independently selected from the group consisting ofH and C₁-C₂ alkyl;

R³⁰ and R³¹ are each independently selected from the group consisting ofH, —OH, C₁-C₆alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl and—C(O)NR¹³R¹⁴; or

R³⁰ and R³¹, together with the carbon atom to which they are bothattached, form ═O, ═S, a cyclopropyl ring or ═NR³⁶;

R³² and R³³ are each independently selected from the group consisting ofH and C₁-C₆ alkyl;

R³⁴ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkylor hydroxy(C₂-C₆)alkyl;

R³⁵ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,—P(O)(OH)₂, allyl, hydroxy(C₂-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,—SO₂R¹⁵, or —(CH₂)₂—N(R¹²)—SO₂—R¹⁵;

R³⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,—NO₂, —CN or OR¹²;

R³⁷ is 1 to 3 substituents independently selected from the groupconsisting of H, C₁-C₆ alkyl, —OH, C₁-C₆ alkoxy and halogen;

r is 1 to 3;

X² is —NR³⁵—, —O—, —S—, —S(O)—, —SO₂—, —CH₂—, —CF₂— or —CR¹²F—;

X³ is —NR³⁴—, —N(CONR¹³R¹⁴)—, —N(CO₂R¹³)—, —N(SO₂R¹⁵)—, —N(COR¹²)—,—N(SO₂NHR)—, —O—, —S—, —S(O)—, —SO₂—, —CH₂—, —CF₂— or —CR¹²F—;

n₃ is 1 to 5; and

n₅ is 1 to 3.

The invention comprises at least one compound having the formula (I),including any and all diastereomers, enantiomers, stereoisomers,regiostereomers, rotomers, tautomers and prodrugs of the compoundshaving the formula (I) and their corresponding salts, solvates (e.g.,hydrates), esters, and the like. The compounds having the formula (I)can be useful for treating a variety of diseases, symptoms andphysiological disorders, such as emesis, depression, anxiety and cough.

Another aspect of the invention comprises a pharmaceutical compositioncomprising a compound of formula (I), alone or with another activeagent, and a pharmaceutically acceptable carrier or excipient therefor.The inventive compounds and compositions can be used alone or incombination with other active agents and/or methods of treatment fortreating a variety of diseases, symptoms and physiological disorders,such as the ones disclosed herein.

DETAILED DESCRIPTION

The following definitions and terms are used herein or are otherwiseknown to a skilled artisan. Except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Thesedefinitions apply regardless of whether a term is used by itself or incombination with other terms, unless otherwise indicated. Hence, thedefinition of “alkyl” applies to “alkyl” as well as the “alkyl” portionsof “hydroxyalkyl,” “haloalkyl,” “alkoxy,” etc.

The term “substituted,” as used herein, means the replacement of one ormore atoms, usually hydrogen atoms, in a given structure with an atom orradical selected from a specified group. In the situations where morethan one atom may be replaced with a substituent selected from the samespecified group, the substituents may be, unless otherwise specified,either the same or different at every position.

The term “heteroatom,” as used herein, means a nitrogen, sulfur, oroxygen atom. Multiple heteroatoms in the same group may be the same ordifferent.

The term “alkyl,” as used herein, means a straight or branched,hydrocarbon chain having the designated number of carbon atoms. If thenumber of carbon atoms is not designated, the carbon chain is from oneto twenty-four carbon atoms, more preferably, from one to twelve carbonatoms, and most preferably, from one to six carbon atoms.

The term “cycloalkyl” as used herein, means a saturated, stable,non-aromatic carbocyclic ring having from three to eight carbon atoms.The cycloalkyl may be attached at any endocyclic carbon atom thatresults in a stable structure. Preferred carbocyclic rings have fromthree to six carbons. Examples of cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike.

The term “aryl,” as used herein, means an aromatic, mono- or bicyclic,carbocyclic ring system having from one to two aromatic rings. The arylmoiety will generally have from 6 to 14 carbon atoms with all availablesubstitutable carbon atoms of the aryl moiety being intended as possiblepoints of attachment. Representative examples include phenyl, cumenyl,naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The term “heteroaryl,” as used herein, means a mono- or bicyclic,chemically feasible ring system containing one or two aromatic rings and1 to 4 nitrogen, oxygen or sulfur atoms in the aromatic ring. Typically,a heteroaryl group represents a cyclic group of five or six atoms, or abicyclic group of nine or ten atoms, at least one of which is carbon,and having at least one oxygen, sulfur or nitrogen atom interrupting acarbocyclic ring having a sufficient number of pi (,) electrons toprovide aromatic character. Representative heteroaryl (heteroaromatic)groups are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl,benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isothiazolyl,benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl,1,3,5-triazinyl and indolyl groups. The heteroaryl group can be joinedto the rest of the molecule through a bond at any substitutable carbonor nitrogen.

The term “heterocycloalkyl” as used herein means a saturated cyclic ringhaving from 3 to 8 members, preferably 5 or 6 members, and comprising 2to 7 carbon atoms and 1 to 3 heteroatoms independently selected from thegroup consisting of —O—, —S—, —S(O)—, —SO₂— and —NR³⁵—. Typicalheterocycloalkyl rings are pyrrolidinyl, imidazolidinyl, piperidinyl,piperazinyl, morpholinyl, and the like. The heterocycloclkyl ring can beattached to the rest of the structure through either a substitutablering carbon or a substitutable ring nitrogen.

The term “heterocycloalkenyl” as used herein means a cyclic ring havingfrom 3 to 8 members, preferably 5 or 6 members, and comprising 2 to 7carbon atoms and 1 to 3 heteroatoms independently selected from thegroup consisting of —O—, —S—, —S(O)—, —SO₂— and —NR³⁵—, and having atleast one double bond in the ring, but not having aromaticcharacteristics. Examples of such rings are:

wherein the ring can be attached to the rest of the structure througheither a substitutable ring carbon or a substitutable ring nitrogen(e.g., in R⁴, when G is heterocycloalkenyl, it can be joined to the(CR²⁸R²⁹)_(n1) group through either a substitutable ring carbon or asubstitutable ring nitrogen).

When R⁴ and R⁵form a ring with 1, 2 or 3 groups independently selectedfrom X², and 1 or 2 of X² are carbon, the variable size of the ring canbe defined by n₄ and n₇, which are independently selected from 0-5,provided that the sum of n₄ and n₇ is 1 to 5. A typical structurewherein the heteroatom is —NR³⁵—, X² is —CH₂—, and R³⁰ and R³¹ togetherform a carbonyl group is represented by the formula

When R⁴ and R⁵, together with the carbon to which they are attached,form a heterocycloalkenyl ring, examples of such rings are

The term “alkoxy,” as used herein, means an oxygen atom bonded to ahydrocarbon chain, such as an alkyl or alkenyl group (e.g., —O-alkyl or—O-alkenyl). Representative alkoxy groups include methoxy, ethoxy, andisopropoxy groups.

The term “hydroxyalkyl,” as used herein, means a substituted hydrocarbonchain, preferably, an alkyl group, having at least one hydroxysubstituent (i.e., —OH). Representative hydroxyalkyl groups includehydroxymethyl, hydroxyethyl and hydroxypropyl groups.

The term “halo” or “halogen” as used herein means a chloro, bromo,fluoro or iodo atom radical.

Unless otherwise known, stated or shown to be to the contrary, the pointof attachment for a multiple term substituent (multiple terms that arecombined to identify a single moiety) to a subject structure is throughthe last named term of the multiple term. For example, an “arylalkyl”substituent attaches to a targeted structure through the “alkyl” portionof the substituent. Conversely, when the substituent is “alkylaryl”, itattaches to a targeted structure through the “aryl” portion of thesubstituent. Similarly, a cycloalkylalkyl substituent attaches to atargeted through the latter “alkyl” portion of the substituent (e.g.,Structure-alkyl-cycloalkyl).

When a variable appears more than once in a structural formula, forexample, R⁸, its definition at each occurrence is independent of itsdefinition at every other occurrence.

The term “prodrug,” as used herein, represents compounds that are drugprecursors which, following administration to a patient, release thedrug in vivo via a chemical or physiological process (e.g., a prodrug onbeing brought to a physiological pH or through an enzyme action isconverted to the desired drug form). A discussion of prodrugs isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of A.C.S. Symposium Series (1987), and in BioreversibleCarriers in Drug Design, E. B. Roche, ed., American PharmaceuticalAssociation and Pergamon Press (1987), each of which is incorporatedherein by reference in its entirety.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Other than as shown in the operating examples or where is otherwiseindicated, all numbers used in the specification and claims expressingquantities of ingredients, reaction conditions, and so forth, areunderstood as being modified in all instances by the term “about.”

Referring to the compound having the formula (I):

or a pharmaceutically-acceptable salt thereof, preferred are compoundswherein

Ar¹ and Ar² are each, preferably,

where R⁸, R⁹ and R¹⁰ are each independently defined as above in thesummary of the invention. More preferably, for Ar², R¹⁰ is H, and R⁸ andR⁹ are independently selected from the group consisting of —CF₃, —CHF₂,—CH₂F, halogen, C₁-C₆ alkyl, —OCF₃ and —OR¹²; for Ar¹, R⁹ and R¹⁰ areindependently selected from the group consisting of H, —OH and halogen.The variable n₂ is preferably 1 or 2.

X¹ is, preferably —O— or —NR³⁴—. More preferably, X¹ is —O—.

R¹ and R² are each, preferably, independently selected from the groupconsisting of H and C₁-C₆ alkyl. More preferably, R¹ and R² are eachindependently selected from the group consisting of H and CH₃.

R³ is preferably selected from the group consisting of H and C₁-C₆alkyl. More preferably, R³ is H.

Each R⁶ is preferably independently selected from the group consistingof H and C₁-C₆ alkyl. Even more preferably, each R⁶ is H.

Each R⁷ is preferably independently selected from the group consistingof H and C₁-C₆ alkyl. Even more preferably, each R⁷ is H.

More preferred are compounds of the structure II

wherein X¹ is —O— or —NR³⁴—; R⁸ and R⁹ are independently selected fromthe group consisting of —CF₃, —CHF₂, —CH₂F, halogen, C₁-C₆ alkyl, —OCF₃and —OR¹²; R⁹ andR¹⁰ are independently selected from the group consisting of H, —OH andhalogen; and n₂ is 1 or 2.

Preferred compounds of formula I and formula II are those wherein one ofR⁴ and R⁵ is H and the other is —C(R²⁸R²⁹)_(n1)-G, wherein n, is 0, 1 or2. More preferred are compounds wherein one of R⁴ and R⁵ is H and theother is selected from the group consisting of —NR¹³R¹⁴, —NR¹²C(O)R¹⁴,—C(O)NR¹³R¹⁴, —OC(O)R¹⁴, —OC(O)NR¹³R¹⁴, NR¹²C(O)OR¹³, —C(O)OR¹³,—NR¹²(C(O)NR¹³R¹⁴), —NR¹²SO₂R¹³, —SO₂NR¹³R¹⁴, R¹⁹-heteroaryl,

Even more preferred are such compounds wherein R¹² and R²⁷ areindependently selected from the group consisting of H and C₁-C₆ alkyl,especially H and —CH₃, and more especially, both are H; n₃ is 2 or 3;and n₅ is 1 or 2.

In another embodiment, preferred compounds of formula I and formula IIare those wherein R⁴ is —NR¹³R¹⁴, —NR¹²C(O)R¹⁴, NR¹²C(O)OR¹³,—NR¹²(C(O)NR¹³R¹⁴), —OH, —O—(C₁-C₆)alkyl, —O—(C₃-C₈)cycloalkyl,—OC(O)R¹⁴, —OC(O)NR¹³R¹⁴, —NR¹²SO₂R¹³, —SO₂NR¹³R¹⁴, R¹⁹-heteroaryl,

wherein X₂ is —O—, —S—, —CH₂— or —NR³⁵—; and R⁵ is —C(O)OR¹³ or—C(O)NR¹³R¹⁴. More preferred are compounds wherein R¹² is independentlyselected from the group consisting of H, C₁-C₆ alkyl and C₃-C₈cycloalkyl; R²⁷ is H; n₃ is 2 or 3; and n₅ is 1 or 2.

Still another preferred embodiment of compounds of formula I and II isthat wherein R⁴ and R⁵, together with the carbon atom to which they areboth attached, form a 4- to 8-membered heterocycloalkyl orheterocycloalkenyl ring containing 1 to 3 groups independently selectedfrom X², provided that at least one X² is —NR³⁵—, —O—, —S—, —S(O)— or—SO₂—, the ring being optionally substituted with from 1 to 6substituents independently selected from the group consisting of R³⁰ andR³¹;. More preferred are compounds wherein the 4- to 8-membered ring isselected from the group consisting of:

wherein R³⁵ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl; n₅ is 1, 2 or 3;X² is —NR³⁵—, —CH₂—, —O— or —S—; R³⁰ is H, C₁-C₆ alkyl or C₃-C₈cycloalkyl; and R³¹ is H, —OH or C₁-C₆ alkyl. Especially preferred are4- to 8-membered rings selected from the group consisting of

The rings are optionally substituted with R³⁰ and R³¹.

Yet another group of preferred compounds wherein R⁴ and R⁵ form a ringis that wherein the ring is selected from the group consisting of

wherein R³⁰ is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R³¹ is H, —OH orC₁-C₆ alkyl; each R³⁵ is independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl and hydroxy(C₁-C₆)alkyl; n₄ and n₇ areindependently 0-5, provided that the sum of n₄ and n₇ is 1-5. Especiallypreferred are 4- to 8-membered rings selected from the group consistingof

The rings are optionally substituted with R³⁰ and R³¹.

In still another embodiment of the invention, it is preferable for atleast one of R⁴ and R⁵ to be in a cis orientation to the Ar¹substituent.

R¹⁵ is preferably C₁-C₆ alkyl or —CF₃. More preferably, R¹⁵ is C₁-C₆alkyl.

R¹⁸ is preferably H or —C₁-C₆ alkyl. More preferably, R¹⁸ is H or CH₃.Even more preferably, R¹⁸ is H.

Each R¹⁹ is a substituent on the aryl or heteroaryl ring to which it isattached, and is, preferably, independently selected from the groupconsisting of H, C₁-C₆ alkyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂ and—OCH₂F. More preferably, each R¹⁹ is selected from the group consistingof H and C₁-C₆ alkyl.

Preferably, r is 1 or 2. More preferably, r is 1.

R²¹ and R²² are each, preferably, independently selected from the groupconsisting of H and C₁-C₆ alkyl. More preferably, R²¹ and R²² are eachindependently selected from the group H and CH₃.

R²³ and R²⁴ are each, preferably, independently selected from the groupconsisting of H and C₁-C₆ alky, or R²³ and R²⁴ together are ═O. Morepreferably, R²³ and R²⁴ are each independently selected from the group Hand CH₃.

R²⁸ and R²⁹ are preferably, independently selected from the groupconsisting of H and —CH₃.

R³⁰ and R³¹ are preferably independently selected from the groupconsisting of H and C₁-C₂ alkyl, or R³⁰ and R³¹ together are ═O. Morepreferably, R³⁰ and R³¹ are each independently selected from the groupconsisting of H and —CH₃.

R³² and R³³ are preferably independently selected from the groupconsisting of H and —CH₃ Even more preferably, R³² and R³³ are each H.

R³⁶ is preferably H or C₁-C₆ alkyl. More preferably, R³⁶ is H or —CH₃.

R³⁷ is preferably 1 or 2 substituents selected from the group consistingof H, —CH₃ and halogen.

Preferred compounds of the invention are those shown below in Examples3, 9, 12a, 13, 14, 15, 20, 23, 29, 36, 40, 43b, 44b, 45, 50, 53, 56b,57, 60a, 61, 62, 63, 72a, 73b, 74a, 75b, 76a, 82a, 82b, 90, 96, 105,106b, 109, 110a, 111a, 112 and 113. More preferred are compounds ofExamples 12a, 43b, 72a, 73b, 109, 110a and 111a.

Compounds having the formula (I) can be effective antagonists of the NK₁receptor, and of an effect of its endogenous agonist, Substance P, atthe NK₁ receptor site, and therefore, can be useful in treatingconditions caused or aggravated by the activity of said receptor. The invitro and in vivo NK₁, NK₂ and NK₃ activities of the compounds havingthe formula (I) can be determined by various procedures known in theart, such as a test for their ability to inhibit the activity of the NK₁agonist Substance P. The percent inhibition of neurokinin agonistactivity is the difference between the percent of maximum specificbinding (“MSB”) and 100%. The percent of MSB is defined by the followingequation, wherein “dpm” represents “disintegrations per minute”:

${\%\mspace{14mu}{MSB}} = {\frac{\begin{matrix}{\left( {{dpm}\mspace{14mu}{of}\mspace{14mu}{unknown}} \right) -} \\\left( {{dpm}\mspace{14mu}{of}\mspace{14mu}{nonspecific}\mspace{14mu}{binding}} \right)\end{matrix}}{\begin{matrix}{\left( {{dpm}\mspace{14mu}{of}\mspace{14mu}{total}\mspace{14mu}{binding}} \right) -} \\\left( {{dpm}\mspace{14mu}{of}\mspace{14mu}{nonspecific}\mspace{14mu}{binding}} \right)\end{matrix}} \times 100.}$The concentration at which the compound produces 50% inhibition ofbinding is then used to determine an inhibition constant (“Ki”) usingthe Chang-Prusoff equation.

In vivo activity may be measured by inhibition of an agonist-inducedfoot tapping in a gerbil, as descibed in Science, 281, 1640-1695 (1998),which is herein incorporated by reference in its entirety. It will berecognized that compounds having the formula (I) can exhibit NK₁antagonist activities of varying degrees. For instance, certaincompounds can exhibit stronger NK₁ antagonist activities than others.

The compounds of the invention exhibit potent affinities for the NK₁receptor as measured by Ki values (in nM). The activities (potencies)for the compounds of the invention are determined by measuring their Kivalues. The smaller the Ki value, the more active is a compound forantagonizing the NK₁ receptor. Compounds of the invention exhibit a widerange of activities. The NK₁ average Ki values for compounds having theformula (I) generally range from 0.01 nM to about 1000 nM, preferably,from about 0.01 nM to about 500 nM, with values of from about 0.01 nM toabout 100 nM being more preferred. Even more preferred are compoundshaving average Ki values of from 0.01 nM to about 10 nM for the NK₁receptor. The most preferred compounds have NK₁ average Ki values offrom 0.01 nM to about 3 nM. The preferred compounds noted above have thefollowing Ki values: Example 43b: 0.77 nM; 72a: 0.66 nM; 73b: 0.2 nM;109: 0.1 nM; 110a: 0.41 nM; and 111a: 0.38 nM.

The inventive compounds are also highly selective for antagonizing a NK₁receptor as opposed to antagonizing (i) NK₂ and/or (ii) NK₃ receptors.When a compound's selection ratio is greater than about 100 for the Kiof the NK₁ receptor to the Ki of the NK₂ receptor, and/or,independently, the Ki of the NK₃ receptor, then the compound is definedherein as a selective antagonist of the NK₁ receptor, as opposed to theNK₂ and/or NK₃ receptors, respectively.

Compounds having the formula (I) may have at least one asymmetricalcarbon atom. All isomers, including stereoisomers, diastereomers,enantiomers, regiostereomers, tautomers and rotational isomers, arecontemplated as being part of the invention. Prodrugs, salts, solvates,esters, etc., derived from the compounds having the formula (I) orprecursors thereof are also within the scope of the invention. Theinvention includes d- and I-isomers in pure form and in admixture,including racemic mixtures. Isomers can be prepared using conventionaltechniques, either by reacting optically pure or optically enrichedstarting materials or by separating isomers of a compound having theformula (I). Those skilled in the art will appreciate that for somecompounds having the formula (I), particular isomers can show greaterpharmacological activity than other isomers.

There are many uses for the compounds having the formula (I). Forinstance, compounds having the formula (I) can be useful as antagonistsof neurokinin receptors, particularly, NK₁ receptors in a mammal, suchas a human. As such, they may be useful in treating and preventing oneor more of a variety of mammalian (human and animal) disease states(physiolgical disorders, symptoms and diseases), for instance,respiratory diseases (e.g., chronic lung disease, bronchitis, pneumonia,asthma, allergy, cough and bronchospasm), inflammatory diseases (e.g.,arthritis and psoriasis), skin disorders (e.g., atopic dermatitis andcontact dermatitis), ophthalmalogical disorders (e.g., retinitis, ocularhypertension and cataracts), central nervous system conditions, such asdepressions (e.g., neurotic depression), anxieties (e.g., generalanxiety, social anxiety and panic anxiety disorders), phobias (e.g.,social phobia), and bipolar disorder, addictions (e.g., alcoholdependence and psychoactive substance abuse), epilepsy, nociception,psychosis, schizophrenia, Alzheimer's disease, AIDs related dementia,Towne's disease, stress related disorders (e.g., post tramautic stressdisorder), obsessive/compulsive disorders, eating disorders (e.g.,bulemia, anorexia nervosa and binge eating), mania, premenstrualsyndrome, gastrointestinal disorders (e.g., irritable bowel syndrome,Crohn's disease, colitis, and emesis), atherosclerosis, fibrosingdisorders (e.g., pulmonary fibrosis), obesity, Type II diabetes, painrelated disorders (e.g., headaches, such as migraines, neuropathic pain,post-operative pain, and chronic pain syndromes), bladder andgenitourinary disorders (e.g., interstitial cystitis and urinaryincontinence), and nausea. In particular, the compounds having theformula (I) are useful for treating disease states related tomicrovascular leakage and mucus secretion. Consequently, the compoundsof the invention are especially useful in the treatment and preventionof asthma, emesis, nausea, depressions, anxieties, cough and painrelated disorders.

In still another aspect of the invention, a method is provided forantagonizing an effect of a Substance P at a neurokinin-1 receptor siteor for the blockade of one or more neurokinin-1 receptors in a mammal inneed of such treatment, comprising administering to the mammal aneffective amount of at least one compound having the formula (I).

In another embodiment of the invention, an effective amount of one ormore of the inventive NK₁ receptor antagonists may be combined with aneffective amount of one or more selective serotonin reuptake inhibitors(“SSRIs”) to treat depression or anxiety. SSRIs alter the synapticavailability of serotonin through their inhibition of presynapticreaccumulation of neuronally released serotonin. U.S. Pat. No.6,162,805, which is incorporated herein by reference in its entirety,discloses a method for treating obesity with a combination therapy of aNK₁ receptor antagonist and an SSRI. An inventive compound(s) having theformula (I) can be combined together with an SSRI(s) in a singlepharmaceutical composition or it can be administered simultaneously,concurrently or sequentially with an SSRI.

Numerous chemical substances are known to alter the synapticavailability of serotonin through their inhibition of presynapticreaccumulation of neuronally released serotonin. Representative SSRIsinclude, without limitation, the following: fluoxetine, fluvoxamine,paroxetine, sertaline, and pharmaceutically-acceptable salts thereof.Other compounds can readily be evaluated to determine their ability toselectively inhibit serotonin reuptake. Thus, the invention relates to apharmaceutical composition comprising at least one NK₁ receptorantagonist having the formula (I) and at least one SSRI, and a method oftreating the above identified mammalian disease states, the methodcomprising administering to a patient in need of such treatment aneffective amount of the pharmaceutical composition comprising at leastone NK₁ receptor antagonist having the formula (I) in combination withat least one SSRI, such as one of those recited above.

In another aspect, the invention relates to a method of treating emesis,comprising administering to a patient in need of such treatment aneffective amount of at least one NK₁ receptor antagonist having theformula (I). Compounds of the present invention are particularly usefulin treating delayed onset emesis such as that experienced 24 hours toseveral days after the administration of chemotherapy. See Gonzales etal, Oncology Special Edition, Vol. 5 (2002), p. 53-58. Combinations ofat least one NK₁ receptor antagonist and at least one other anti-emeticagent such as a serotonin 5-HT₃ receptor antagonist, a corticosteroid ora substituted benzamide can be used to treat other forms of emesis,e.g., acute emesis induced by chemotherapy, radiation, motion andalcohol (e.g., ethanol), and post-operative nausea and vomiting.Examples of serotonin 5-HT₃ receptor antagonists are palonsetron,dolasetron, ondansetron and granisetron, or apharmaceutically-acceptable salts thereof. An examples of a suitablecorticosteroid is dexamethasone. An example of a substituted benzamideis metoclopramide.

Preferred combinations for the treatment of emesis include a compound offormula I and a serotonin 5-HT₃ receptor antagonist; a compound offormula I and a corticosteroid; a compound of formula I and asubstituted benzamide; a compound of formula I, a serotonin 5-HT₃receptor antagonist and a corticosteroid; and a compound of formula I, asubstituted benzamide and a corticosteroid.

When an inventive NK₁ receptor antagonist is combined with an SSRI, aserotonin 5-HT₃ receptor antagonist, a corticosteroid or a substitutedbenzamide for administration to a patient in need of such treatment, thetwo or more active ingredients can be administered simultaneously,consecutively (one after the other within a relatively short period oftime), or sequentially (first one and then the other over a period oftime).

Thus, the compounds of the invention may be employed alone or incombination with other agents. In addition to the above described NK₁receptor antagonist/SSRI or serotonin 5-HT₃ receptor antagonistcombination therapy, the compounds having the formula (I) may becombined with other active agents, such as other types of NK₁ receptorantagonists, prostanoids, H₁ receptor antagonists, α-adrenergic receptoragonists, dopamine receptor agonists, melanocortin receptor agonists,endothelin receptor antagonists, endothelin converting enzymeinhibitors, angiotensin II receptor antagonists, angiotensin convertingenzyme inhibitors, neutral metalloendopeptidase inhibitors, ET_(A)antagonists, renin inhibitors, serotonin 5-HT_(2c) receptor agonists,nociceptin receptor agonists, rho kinase inhibitors, potassium channelmodulators and/or inhibitors of multidrug resistance protein 5.Preferable therapeutic agents for combination therapy with compounds ofthe invention are the following: prostanoids, such as prostaglandin E₁;α-adrenergic agonists, such as phentolamine mesylate; dopamine receptoragonists, such as apomorphine; angiotensin II antagonists, such aslosartan, irbesartan, valsartan and candesartan; and ET_(A) antagonists,such as bosentan and ABT-627. Dosage ranges for the other agent can bedetermined from the literature.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington: The Science and Practice ofPharmacy, 20^(th) Edition, (2000), Lippincott Williams & Wilkins,Baltimore, Md.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparations subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.01 mg to about 4,000 mg, preferably fromabout 0.02 mg to about 1000 mg, more preferably from about 0.03 mg toabout 500 mg, and most preferably from about 0.04 mg to about 250 mgaccording to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill in the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.02mg/day to about 2000 mg/day, in two to four divided doses.

The quantity of NK₁ receptor antagonist in combination with a SSRI orserotonin 5-HT₃ receptor antagonist (5-HT₃) in a unit dose ofpreparation may be varied or adjusted from about 10 to about 300 mg ofNK₁ receptor antagonist combined with from about 10 to about 100 mg ofSSRI or 5-HT₃. A further quantity of NK₁ receptor antagonist incombination with a SSRI or 5-HT₃ in a unit dose of preparation may bevaried or adjusted from about 50 to about 300 mg of NK₁ receptorantagonist combined with from about 10 to about 100 mg of SSRI or 5-HT₃.An even further quantity of NK₁ receptor antagonist in combination withSSRI or 5-HT₃in a unit dose of preparation may be varied or adjustedfrom about 50 to about 300 mg of NK₁ receptor antagonist combined withfrom about 20 to about 50 mg of SSRI or 5-HT₃, depending on theparticular application. Dosage levels for the corticosteroids andsubstituted benzamides can be determined form the literature.

Alternatively, separate dosage forms of the compounds of formula I andthe other agents can be provided in a single package as a kit for theconvenience of the patient. This is particularly useful when theseparate components must be administered in different dosage forms(e.g., a tablet and a capsule) or at different dosage schedules.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of the invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained. When thesymptoms have been alleviated to the desired level, treatment shouldcease. Patients may, however, require intermittent treatment on along-term basis upon any recurrence of disease symptoms.

The inventive compounds can exist in unsolvated as well as solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically-acceptable solvents, such as water, ethanol, and thelike, are equivalent to the unsolvated forms for purposes of thisinvention.

The inventive compounds may form pharmaceutically-acceptable salts withorganic and inorganic acids. Examples of suitable acids for saltformation are hydrochloric, sulfuric, phosphoric, acetic, citric,malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose skilled in the art. The salts are prepared by contacting the freebase forms with a sufficient amount of the desired acid to produce asalt in a conventional manner. The free base forms may be regenerated bytreating the salt with a suitable dilute aqueous base solution, such asdilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodiumbicarbonate. The free base forms may differ somewhat from theirrespective salt forms in certain physical properties, such as solubilityin polar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

Acidic compounds of the invention (e.g., those compounds which possess acarboxyl group) form pharmaceutically-acceptable salts with inorganicand organic bases. Representative examples of such types of salts aresodium, potassium, calcium, aluminum, gold and silver salts. Alsoincluded are salts formed with pharmaceutically-acceptable amines, suchas ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine, and thelike.

Following are general and specific methods of preparing compounds havingthe formula (I). As used herein, the following abbreviations are definedas follows:

-   -   RBF is a round bottom flask;    -   RT is room temperature;    -   Me is methyl;    -   Bu is butyl;    -   Ac is acetyl;    -   Et is ethyl;    -   Ph is phenyl;    -   THF is tetrahydrofuran;    -   OAc is acetate;    -   (Boc)₂O is di-tert-butyl dicarbonate;    -   (Boc) is tert-butoxy carbonyl;    -   TLC is thin layer chromatography;    -   LAH is lithium aluminum hydride;    -   LDA is lithium diisopropyl amine;    -   CDI is 1,1-carbonyl diimidazole;    -   HOBT is hydroxybenzotriazole;    -   DEC is 1[3-(dimethylamino)propyl]-3-ethylcarbodiimide        hydrochloride;    -   TFA is trifluoroacetic acid;    -   MTBE is t-butyl methyl ether;    -   DIEA or i-Pr₂EtN is diisopropylethyl amine;    -   Prep plate is preparative thin layer chromatography;    -   DMF is dimethyl formamide    -   DMPU is 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone    -   TEMPO is a free radical of 2,2,6,6-tetra        methyl-1-piperidinyloxy;    -   BuLi is butyl lithium;    -   KHMDS is potasium bis(trimethylo silyl)amide; and    -   DBU is 1,8-diazabicyclo[5.4.0]un dec-7-ene.

Compounds having the formula (I) can be prepared using methods known tothose skilled in the art. Typical procedures are described below,although a skilled artisan will recognize that other procedures may beapplicable, and that the procedure may be suitably modified to prepareother compounds within the scope of formula (I).

General Methods of Preparation

Compounds having the formula (I) may be generally prepared from thecorresponding protected oxazolidinone derivative A₁ as shown under thefollowing conditions, where Ar¹ and Ar² are each defined as in thesummary of the invention; X¹ is —O—; R¹ through R³³, independently ofone another, are each defined as in the summary of the invention; and n₂is 1.

The stereoselective alkylation of a protected oxazolidinone A1 providesthe protected oxazolidinone A2. Partial reduction with a reducing agent,such as LAH, provides the lactol A3. A Wittig reaction provides thecorresponding olefin A4. Hydrogenation of the olefin A4 and cyclizationprovides the lactam A5. If the protecting group (Pr) on the nitrogen isCbz then it might cleave under hydrogenation conditions. Thedeprotection of the nitrogen of the lactam A5, if necessary, followed byreduction of the lactam with reducing agents such as LAH or LAH/AlCl₃,preferably LAH/AlCl₃, provides substituted pyrrolidines A6.

Compounds having the formula I, where n₂ is 1 and R⁴ is —NR¹³R¹⁴,—NR¹²SO₂R¹³, —NR¹²C(O)R¹⁴, or —NR¹²(C(O)NR¹³R¹⁴) can also be prepared byconversion of lactol A3 to olefin A7 via Wittig reaction using anitrogen protected (NPr′) glycine ester Wittig reagent where Pr′ can bea Boc or Cbz protecting group and Pr is preferably a Cbz protectinggroup. Palladium catalyzed hydrogenation and deprotection (if Pr is aCbz group) of olefin A7, followed by spontaneous cyclization willprovide lactam A8. When Pr is not Cbz or a protecting group readilycleaved under standard hydrogenation conditions, then hydrogenation ofthe olefin A7 is followed by deprotection of —NHPr and subsequentcyclization to provide lactam A8. The deprotection of the N—Pr′ group,if necessary, followed by the reduction of the lactam with reducingagents as LAH or LAH/AlCl₃, preferably LAH/AlCl₃, providesamino-pyrrolidines A9 which can further be functionalized using standardconditions to give N-substituted pyrrolidines A10.

Those skilled in the art will appreciate that the stereoselectivehydrogenation of the double bond of olefin A7 are can also be performedusing a chiral hydrogenation catalyst such as chiral Rhodium catalystwhich can provide chiral ester A11. Deprotection of the protecting group(if Pr, Pr′ are Cbz groups) under standard hydrogenation conditionsfollowed by spontaneous cyclization will provide chiral amino-lactamA12. The reduction of the chiral amino-lactam A12 with reducing agentsas LAH or LAH/AlCl₃, preferably, LAH/AlCl₃, provides chiralamino-pyrrolidines A13 which can further be functionalized usingstandard conditions to give N-substituted pyrrolidines A14.

Compounds having the formula I, where n₂ is 2, 3 or 4, may be preparedby conversion of the lactol A3 to carbon homologated derivatives A15 (nis 1, 2 or 3) using routine chemistry known to those skilled in the art.Particularly useful reagents for this carbon chain homologation include:Wittig chemistry using methoxymethyl triphenylphosphonium bromide or ananalogous reagent, cyanomethyl triphenylphosphonium bromide andHorner-Emmons protocols, and aldol chemistry. Hydrogenation andcyclization to the 6-, 7- and 8-membered lactams A17, respectively, anddeprotection and reduction to the 6-, 7- and 8-membered substitutedreduced lactams A18, are analogous to the previously describedprocedures.

Another method for preparing aldehyde A15 where R⁶, R⁷═H involves Wittighomologation of lactol A3 to ethylene derivative A19 which uponhydroboration, preferably with 9-BBN, and subsequent oxidation providesaldehyde A20.

Alternatively, compounds having the formula I, where n₂ is 2, and X¹ is—O— can be prepared by means of transformation of ketone A21 to thesulfinamide using the appropriate sulfinamide (racemic or chiral) andtitaniumisopropoxide, according to the protocol described in Cogan etal, Tetrahedron, 55, 8883 (1999). The sulfinamide A22 is then treatedwith a suitable allyl grignard reagent, followed by ozonolysis toprovide the aldehyde A24. Those skilled in the art will recognize thataddition of allyl grignard will provide A23 where R⁶, R⁷═H which can befurther modified at the allylic position to incorporate functionalitiesfrom the definition of R⁶ and R⁷ using routine chemistry such asalkylation and hydroxylation. Wittig chemistry on aldehyde A24, followedby hydrogenation, deprotection and cyclization provides the lactam A26.Standard reduction of the lactam A26 provides the substitutedpiperidines A27, where n₂ is 2.

When X¹ is as defined in the summary of the invention, the ketone A21wherein X¹ is an ether, thio or imino group may be prepared usingseveral different methods employing commercially available materials.Ketone A28 can be subjected to acylation (Q¹ is —NH₂, —OH or —SH),reductive amination (Q¹ is —NH₂), ether formation (Q¹ is —OH) bystandard alkylation methods, thio ether formation (Q¹ is —SH) bystandard alkylation methods, or esterification (Q¹ is —OH or —SH).Alternatively, the corresponding alcohol A29 can be oxidized to analdehyde and treated with an aryl or heteroaryl organometallic reagent,followed by oxidation to give ketone A21.

Another method for preparing ketone A21 involves nucleophilicdisplacement of a leaving group, such as —Cl, —Br, —I, —OMs and —OTf,adjacent to the aryl or heteroaryl ketone, for example, see WO 01/44200(2001), which is incorporated herein in its entirety by reference.Accordingly, a suitable substituted styrene or heteroaryl epoxide may beopened with the appropriate nucleophile to give the desired X¹:

Compounds having the formula I where n₂ is 2 and R⁴ or R⁵ is —NR¹³R¹⁴,—NR¹²SO₂R¹³, —NR¹²C(O)R¹⁴, or —NR¹²(C(O)NR¹³ R⁴) can also be preparedfrom aldehyde A15 using the chemistry as described earlier for thepyrrolidine compounds (n₂=1).

Those skilled in the art will appreciate that the stereoselectivehydrogenation of the double bond of olefin A32 can also be performedusing a chiral hydrogenation catalyst such as chiral Rhodium catalystwhich can provide chiral ester A36. The chiral ester A36 can beconverted to chiral functionalized amino-piperidine compounds A39 usingthe chemistry as described earlier for the chiral functionalizedamino-pyrrolidine compounds (n₂=1).

Those skilled in the art will appreciate that homologation of thealdehyde A15 followed by subsequent synthetic operations as describedabove will result in the cyclic reduced lactams, where n₂ is 3 or 4.

Another method of preparing compounds having the formula I, where n₂ is2, and X¹ is —O—, involves the alkyation of amine derivative A40 with asuitable substituted allylic halide, preferably a 2-substituted allylicbromide, to bis olefin A41. Treatment of the bis olefin A41 with Grubb'sor Schrock's catalyst using standard olefin metathesis conditionsprovides the unsaturated piperidine derivative A42. Deprotection of thenitrogen and hydrogenation provides the six-membered cyclic reducedlactams or substituted piperidines A43. If the protecting group (Pr) onthe nitrogen is Cbz, then it might cleave under hydrogenationconditions. Those skilled in the art will appreciate that alkylation ofamine A40 with an appropriate substituted alkyl halide of 4 to 5 carbonatoms in length containing a terminal olefin, followed by subsequentsynthetic operations as described above will result in the substitutedcyclic reduced lactams, where n₂ is 3 or 4.

When R⁴═COOCH₃, the chemistry as described above provides A46 whereester group could be further transformed to other functional groups suchas amide (R⁴═CONR¹³R¹⁴) and alcohol (R⁴═CH₂OH) using standard chemistry.In addition, the piperidine A46 can be further functionalized usingchemistry such as alkylation followed by deprotection of the nitrogen,if necessary, to provide substituted piperidines A47.

Another method of preparing compounds having the formula (I), where n₂is 1, X¹ is —O— and R⁴is —OH, —O—(C₁-C₆ alkyl), —O—(C₃-C₈ cycloalkyl),—O—(C₁-C₆ alkyl)-(C₃-C₈ cycloalkyl), —OC(O)R , or —OCONR¹³R⁴, fromlactol A3 involves Wittig chemistry to provide the corresponding olefinester A48. Hydrogenation of the olefin ester A48, followed by reductionto the alcohol using metal hydride reducing agents, preferably LiBH₄,and subsequent oxidation, such as Swern or bleach, gives aldehyde A50.The cyclization of aldehyde A50 provides enamide A51 which uponhydroxylation, preferably using a borane gives alcohol A52. The alcoholA52 can be oxidized under standard oxidation conditions such as Swernoxidation to give ketone A53. Treatment of the ketone with a suitableorganometallic reagent provides the tertiary alcohol A54. For instanceswhere the desired R⁵ substituent cannot be incorporated directly with anorganometallic reagent, further functionalization at the R⁵ position maybe necessary. The hydroxyl group of alcohol A54 can be furtherfunctionalized using standard chemistry followed by deprotection to givedisubstituted pyrrolidines A55. Alternatively, the further modificationof the secondary alcohol A52 under standard conditions and deprotectionof the nitrogen provides the monosubstituted pyrrolidines A56.

Compounds having the formula I, where n₂ is 2, X¹ is —O— and R⁴ is —OH,—O—(C₁-C₆ alkyl), —O—(C₃-C₈ cycloalkyl), ), —O—(C₁-C₆ alkyl)-(C₃-C₈cycloalkyl), —OC(O)R¹⁴ or —OCONR¹³R¹⁴, can be prepared from lactol A3.Wittig chemistry followed by hydrogenation and cyclization in weaklyacidic conditions such as p-toluenesulfonic acid provides the enamideA59. Using the synthetic operations as described above from the enamideA51, the enamide A59 will result in the disubstituted piperidines A63and monosubstituted piperidines A64.

Those skilled in the art will appreciate that homologation of the lactolA3 to the aldehyde A15 where n₂ is 2 or 3 followed by subsequentsynthetic operations as described above will result in themonosubstituted cyclic amines A64 or disubstituted cyclic amines A63where n₂ is 2 or 3.

The compounds having the formula I, where n₂ is 1, 2, 3 or 4, X¹ is —O—and, R⁴ and R⁵, together with the carbon to which they are bothattached, form a chemically feasible 5 membered ring can be preparedfrom corresponding ketones. The ketone A65 is transformed into thecorresponding hydantoin A66 by heating with KCN/ammonium carbonate inethanol/water mixture or by using alternate standard conditions known tothose skilled in the art. The amine is deprotected to give hydanotin A67which can be converted to corresponding urea analogs A68 by reductionpreferably with LAH/AlCl₃. Alternatively hydanotin A66 can be cleaved toamino-acid A69 using the protocol described in Kubik, S.; Meissner, R.S.; Rebek, J. Tetrahedron Lett. 35, 6635 (1994). Standard protection ofthe amino-acid A69 as a carbamate derivative (Pr′) is followed byactivation of the carboxylic acid. Treatment with phosgene or a phosgeneequivalent, preferably triphosgene, is one such method for acidactivation. The reduction of NBoc-UNCA A71 with reducing agents,preferably lithium borohydride, gives alcohol A72 which can be convertedto five membered cyclic compounds such as carbamate A73 byintramolecular cyclization (if Pr′ is carbamate protecting group such asBoc) using base, preferably NaH, followed by deprotection.Alternatively, alcohol A72 can be oxidized to NBoc-aldehyde A74 bystandard oxidation conditions such as Swern oxidation and using theroutine chemistry known to those skilled in the art. The NBoc-aldehydeA74 can be converted to cyclic analogs such as the y-lactam A75.

The compounds having the formula I, where n₂ is 1, 2, 3, or 4, X¹ is —O—and R⁴ is —NR¹³R¹⁴, —NR¹²SO₂R¹³, —NR¹²COR¹⁴, —NR¹²C(O)OR¹³, or—NR¹²(CONR¹³R¹⁴), and R⁵ is —C(O)NR¹³R¹⁴ can be prepared by amidation ofamino-acid A69 to give amino-amide A76 followed by functionalization ofamino group and deprotection to provide disubstituted analogs A77.Alternatively, the NBoc-amino-acid A70 can be reacted with an amine,followed by deprotection of N—Pr′ group to give amino-amide A76. Theamino-amide A76 can also be deprotected to give analogs A78 where R⁴ is—NR¹³R¹⁴ and R¹³, R¹⁴═H.

Another method of preparing compounds having the formula I, where n₂ is1, 2, 3 or 4, X¹ is —O— and R¹⁴ is —NR¹³R¹⁴, —NR¹²SO₂R¹³, —NR¹²COR¹⁴,—NR¹²C(O)OR¹³, or —NR¹²(CONR¹³R¹⁴), involves treatment of ketone A65with a 5 protected amine under appropriate conditions to provide imineA79. Nucleophilic addition of compatible organometallic reagents such asgrignard or reduction (if R⁵═H) of imine A79 followed by deprotection ofnitrogen (N—Pr′) provides amine A80. The functionalization of amine A80under standard conditions and deprotection of nitrogen provides thesubstituted pyrrolidines A81.

The compounds having the formula I, where n₂ is 1, 2, 3 or 4, X¹ is —O—,R⁵ is H, and R⁴ is a heterocyclic or heteroaryl group can be prepared byconversion of ketone A65 to nitrile A87, aldehyde A82 and a carboxylicacid A85 via aldehyde A82 using the standard oxidation conditions. Thosewho are skilled in the art will appreciate that the cyano, aldehyde andcarboxylic acid compounds can provide the appropriate heterocyclic orheteroaryl functionality using standard chemistry.

Another method of preparing the compounds having the formula I, where n₂is 1, 2, 3, or 4, X¹ is —O—, R⁵ is H, and R⁴ is a heterocyclic orheteroaryl group involves conversion of the ketone A65 to a vinyltriflate A89 by using a base such as LDA and triflic anhydride as anelectrophile. The triflate A89 could be coupled with suitableorganometalic reagents, preferably boronic acid, to give heterocyclic orheteroaryl unsaturated compound A90. The reduction of the double bondfollowed by deprotection of the amine (if necessary) providesheterocyclic or heteroaryl substituted cyclic amines A91.

The compounds having the formula I, where n₂ is 1, 2, 3, or 4, X¹ is —O—and R⁴ is —C(OR¹²)(R¹³)(R¹⁴), where R¹⁴ is H, or —C(═NOR¹⁴)(R¹³) can beprepared by conversion of aldehyde A82 to an alcohol A92 via addition ofan organometallic reagent. The alcohol A92 can be transformed to analogssuch as A93 or it can be oxidized to ketone A94 which can providedanalogs such as oxime A95 using the standard conditions.

The compounds having the formula I, where n₂ is 1, 2, 3 or 4, X¹ is —O—,R⁵ is H, and R⁴ is —C(R²⁸R²⁹)CONR¹³R¹⁴, where R²⁸, R²⁹═H or methyl, canbe prepared by conversion of ketone A65 to unsaturated ester A96 usingWittig chemistry. Hydrogenation of the double bond and deprotection ofthe protecting group, if necessary, provides the ester A97. Conversionof the ester to amides A98 can be realized through treatment withamines, or transformation to the acid and subsequent coupling withamines using standard methods. In addition, the unsaturated ester A96can also provide compounds where R⁴ and R⁵, together with the carbon towhich they are attached, form a five membered cyclic ring such as lactamA100.

Those skilled in the art will appreciate that functionalization of thenitrogen of cyclic ring formed by R⁴ and R⁵ when R⁴ and R⁵ together andto the carbon to which they are attached form cyclic rings such ashydantoin A67, urea A68 and lactam A100 may be performed at anappropriate point in the synthesis by deprotonation with a suitable baseand reaction of the necessary electrophile to provide the substitutentsdefined for R³⁵. Those skilled in the art will appreciate that asubstituted alkyl halide will afford the corresponding substituted C₁-C₆alkyl group and treatment with tetrabenzylpyrophosphate, followed byhydrogenation will serve to provide for R³⁵═—P(O)(OH)₂.

Functionalization of the reduced lactam nitrogen can be performed at anappropriate point in the synthesis by deprotonation with a suitable baseand reaction of the necessary electrophile to provide the substitutentsdefined for R¹⁸. Those skilled in the art will appreciate that asubstituted alkyl halide will afford the corresponding substituted C₁-C₆alkyl group and treatment with tetrabenzylpyrophosphate, followed byhydrogenation will serve to provide for R¹⁸═—P(O)(OH)₂.

Those skilled in the art will recognize that certain additionalprotection and deprotection steps may be needed in order to accommodatedifferent functional groups. Accordingly, the order of syntheticoperations may be different in order to maintain functional groupcompatibility with the operational steps in the synthesis.

Specific Methods Of Preparation EXAMPLES

Step 1:

Compound 1 was prepared using a synthetic procedure reported by M. J.O'Donnell, Z. Fang, X. Ma and J. C. Huffman, J. Am. Chem. Soc., 1997,46, 617.

Step 2:

To a nitrogen purged solution of oxazolidinone Compound 1 (10.0 g, 0.027mol, 1equiv) in THF (500 ml) at −78° C., a solution of KHMDS (0.5M intoluene, 64 ml, 0.032 mol, 1.18 equiv) was added. After stirring at −78°C. for 30 min, a solution of bromomethyl ether (11.3 g, 0.032 mol, 1.18equiv) in THF (100 ml) at −78° C. was cannulated into the reactionmixture. The solution was stirred at −78° C. for 1 h before beingquenched with a saturated NH₄Cl solution at −78° C. The reaction mixturewas warmed to RT, and water and EtOAc were added. The aqueous layer wasextracted with EtOAc (200 ml×2). The combined organic layers were dried(MgSO₄) and filtered, and solvents in the filtrate were removed byvacuum. Purification using column chromatography [hexane-toluene, 1:1(v/v)] gave Compound 2 (11.7 g, 68%) as a colorless oil.

Electrospray MS [M+1]⁺ 644.1.

Step 3:

To a solution of lactone Compound 2 (35.2 g, 0.055 mol, 1equiv) in Et₂Oat 0° C., a 1M solution of LAH (17.8 ml, 0.018 mol, 0.32 equiv) in Et₂Owas added. The reaction mixture was stirred at 0° C. for 30 min beforebeing quenched with saturated NH₄Cl solution. Water was added and theresulting layers were separated. The separated aqueous layer wasextracted with EtOAc (300 ml×2), and the combined organic layers weredried (MgSO₄), and filtered. Solvents in the filtrate were removed in avacuum to give a colorless oil. The oil was dissolved in HOAc (240 ml)at RT, and water (60 ml) was added. After being stirred at RT for 1 h,the white solid was filtered, washed with water and dried under a highvacuum. Recrystallization [hexane-toluene] gave Compound 3 (23 g) as awhite powder. All filtrates were combined, and the solvents removed in avacuum to give a yellow oil. The above procedure [HOAc—H₂O, followed byrecrystallization] was repeated to give another batch of lactol Compound3 (3 g). Solvents in the filtrate were removed in a vacuum, and theresulting oil was subjected to column chromatography [hexane-EtOAc,6:1(v/v)] to give a third batch (4 g). The combined yield for Compound 3was 30 g, 87%.

Electrospray MS [M+1]⁺ 646.2.

Step 4:

To a solution of Compound 3 (0.98 g, 1.52mmol, 1 equiv) andNBoc-□-phosphonoglycine trimethylester (1.26 g, 3.80mmol, 2.5 equiv) inCH₂Cl₂ (5 ml) at 23° C., DBU (0.57 ml, 3.80 mmol, 2.5 equiv) was addeddropwise. The mixture was stirred at 23° C. for 4 h before it wasquenched with saturated NH₄Cl solution. Et₂O was added and layers wereseparated. The separated aqueous layer was extracted with Et₂O (250ml×2). The combined organic layers were dried (MgSO₄) and filtered.Removal of solvents in vacuum followed by chromatographic purification[hexane:ether, 3:1 (v/v)] gave Compound 4 (587 mg, 52%) as white foam.

Electrospray MS [M+1]⁺ 745.1.

Step 5:

A solution of Compound 4 (1.4 g, 1.88mmol, 1.0 equiv.) in EtOAc (30 ml)was flushed with N₂. After the addition of Palladium on carbon (10%, 2g) a H₂ balloon was attached to the reaction flask. The reaction mixturewas stirred for 18 h at 23° C. under H₂ atmosphere and then filtered andconcentrated. The residue was dissolved in anhydrous CH₂Cl₂ (45 ml),cooled to 0° C., then treated with TFA solution (4.5 ml, 0.059 mmol,30.0 equiv). The reaction mixture was stirred at 0° C. for 30 min andthen at 23° C. for another 4 h. Reaction mixture was diluted with CH₂Cl₂(300 ml) washed with saturated NaHCO₃ solution (100 ml). The organiclayer was dried (Na₂SO₄), filtered and concentrated to give Compound 5(0.8 g, 95%).

Step 6:

In a flame dry 25 ml RBF was placed AlCl₃ (0.089 g, 0.67 mmol, 1.5equiv). The reaction flask was cooled to 0° C. and 1 M solution of LAHin Et₂O (2 ml, 1.98 mmol, 4.5 equiv) was carefully added. The reactionmixture was cooled to −78° C. and a solution of Compound 5 (0.2 g, 0.44mmol, 1.0 equiv) in dry THF (4 ml) was slowly added. The reactionmixture was stirred at −78° C. for 2 h, then slowly warmed to 23° C. andstirred for 18 h. The reaction was then cooled to 0° C. and quenchedcarefully with saturated aqueous sodium potassium tartrate solution.Reaction mixture was taken up in EtOAc (200 ml) and extracted withsaturated aqueous NaHCO₃ (100 ml). Aqueous layer was extracted withEtOAc (150 ml). The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give Compound 6 (180 mg, 95%). ElectrosprayMS [M+1]⁺ 433.1.

Step 7:

To a solution of Compound 6 (0.21 g, 0.486 mmol, 1.0 equiv) in MeOH (3ml) at 0° C. was added 2-trifluoromethyl-N,N-diacetylaniline (0.131 g,0.535 mmol, 1.1 equiv). The mixture was stirred at 0° C. for 1 h, thenwarmed to 23° C. and stirred for 18 h. The reaction mixture was thenconcentrated and purified using a Gilson with water/CH₃CN to give amixture of two compounds (0.16 g). Purification of the mixture by HPLCusing ChiralPak column (98:2, hexane:IPA) gave less polar isomer Example1a (0.050 g, 22%), Electrospray MS [M+1]⁺ 475.1, and more polar isomerExample 1b (0.015 g, 7%), Electrospray MS [M+1]⁺ 475.1.

Preparation of Compound 9:

Step 1:

Compound 7 was prepared using a procedure similar to that for Compound4, using Compound 3 and PO(OEt)₂CH(NHCbz)CO₂Me in place ofPO(OMe)₂CH(NHBOC)CO₂Me. Electrospray MS [M+1^(]+) 745.1.

Step 2:

Compound 7 (3.0 g, 4.03 mmol, 1.0 equiv) was taken in MeOH (30 ml) in aparr reaction bottle. The reaction bottle was degassed using N₂ for 15min. (+)-1,2-Bis-((2S,5S)-2,5-diethylphospholano) benzene(cyclooctadiene)rhodium(l) trifluoro-methanesulfonate (0.12 g, 0.16mmol, 0.04 equiv) was added to the reaction mixture in a glove box, andshaken under H₂ at 60 psi for 96 h. The reaction mixture was transferredto a 200 ml RBF. 20% of Pd(OH)₂/C (1 g) was added to the reactionmixture, which was stirred under H₂ at 23° C. for 18 h. The reaction wasmonitored by TLC 9/1 EtOAc/CH₃OH. Once the reaction was completed it wasfiltered through celite and concentrated. Purification was carried outusing a silica plug 9:1 EtOAc/MeOH(NH₃) to give the Compound 9 (1.3 g,72%).

Electronspray MS [M+1]⁺ 447.1.

Preparation of Compound 10:

Compound 10 was prepared using similar procedure to Compound 6, usingCompound 9 instead of Compound 5.

Example 2

To a solution of Compound 10 (0.05 g, 0.1 16 mmol, 1.0 equiv) in MeOH (2ml) at −78° C. was added cyclopropanecarbonyl chloride (12□l, 0.127mmol, 1.1 equiv). The mixture was stirred at −78° C. for 5 min, thenwarmed to 23° C. and stirred for 18 h. The reaction mixture was thenconcentrated and taken up in EtOAc (200 ml) and washed with sat. aq.NaHCO₃(1×100 ml). The organic layer was dried over Na₂SO₄, filtered andconcentrated. Purification of the resulting mixture on a Biotage with 5%MeOH/EtOAc gave Example 2 (0.04 g, 69%). Electrospray MS [M+l]⁺ 501.

Example 3

Step 1:

To a solution of Compound 10 (0.05 g, 0.116 mmol, 1.0 equiv) in MeOH (2ml) at −78° C. was added 4-chlorobutyryl chloride (14 μl, 0.127 mmol,1.1 equiv). The mixture was stirred at −78° C. for 5 min, then warmed to23° C. and stirred for 18 h. The reaction mixture was then concentratedand taken up in EtOAc (200 ml) and washed with sat. aq. NaHCO₃(1×100ml). The organic layer was dried over Na₂SO₄, filtered and concentratedto provide the crude Compound 11, which was used in the next reactionwithout further purification.

Step 2:

To a solution of crude Compound 11 in dry THF (2 ml) was added NaH (60%dispersion in mineral oil, 0.014 g, 0.347 mmol, 3 equiv) at 0° C. andstirred for 5 min, then heated at 60° C. for 2 h. The reaction mixturewas cooled to 0° C. and quenched carefully with water (3 ml). Themixture was poured into EtOAc (100 ml) and washed with saturated aqueousNaHCO₃ (100 ml). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. Purification of the resulting mixture onBiotage with 5% MeOH/EtOAc gave Example 3 (0.20 g, 34%).

Electrospray MS [M+1]⁺ 501.1.

Example 4

Example 4 (53% overall yield) was prepared from Compound 10 in a mannersimilar to that used to prepare the Example 3, but using 5-chlorovalerylchloride in place of 4-chlorobutyryl chloride. Electrospray MS [M+1]⁺515.1.

Example 5

To a solution of Compound 9 (0.13 g, 0.29 mmol, 1.0 equiv) in CH₂Cl₂ (3ml) at 0° C. was added DIEA (0.11 ml, 0.61 mmol, 2.1 equiv) and CH₃SO₂Cl(34 μl, 0.435 mmol, 1.5 equiv). The mixture was stirred at 0° C. for 30min, then poured into EtOAc (150 ml) and washed with saturated aqueousNaHCO₃ (100 ml). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated to provide the crude Compound 12, which wasused in the next reaction without further purification.

The crude Compound 12 was converted to Example 5 (80 mg, 54% yield, twosteps from Compound 9) using a method similar to the preparationCompound 6 from Compound 5. Electrospray MS [M+1]⁺ 511.1.

Example 6a and Example 6b

Step 1:

To a solution of amino-lactam Compound 5 (0.100 g, 0.224 mmol, 1 equiv)in toluene (7 ml) at 0° C., was added a solution of 2M AlMe₃ in toluene(0.14 ml, 0.28 mmol, 1.25 equiv). The reaction mixture was warmed to RTand stirred for 15 min. Ethyl 4-bromobutyrate was added, and theresulting mixture was heated at 100° C. for 18 h. The reaction mixturewas cooled to RT, poured into EtOAc (20 ml), and washed with ofsaturated aqueous NaHCO₃ (100 ml) and saturated aqueous NaCl (100 ml)successively. The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated. HPLC separation on ChiralCel OD column usinga (90/10) hexane/IPA mixture gave the Compound 13a (40 mg, 35%), and theCompound 13b (20 mg, 18%).

Electrospray MS [M+1]⁺ 515.1 for the Compound 13a.

Electrospray MS [M+1]⁺ 515.1 for the Compound 13b.

Example 6a and Example 6b were prepared using a procedure similar toCompound 6, using Compound 13a and 13b instead of Compound 5.

Electrospray MS [M+1]⁺ 487.11 for the Example 6a.

Electrospray MS [M+1]⁺ 487.11 for the Example 6b.

Example 7

Example 7 (74% overall yield) was prepared from Compound 10 in a mannersimilar to that used to prepare Example 29 from Example 13.

Electrospray MS [M+1^(]+) 476.1.

Example 8

Example 8 (94% overall yield) was prepared from Compound 10 in a mannersimilar to that used to prepare Example 33 from Example 13.

Electrospray MS [M+1]⁺ 430.1.

Example 9

Example 9 (50% overall yield) was prepared from Compound 10 in a mannersimilar to that used to prepare Example 36 from Example 13.

Electrospray MS [M+1]⁺ 502.1.

Example 10

To a solution of Compound 10 (0.15 g, 0.3 mmol, 1 equiv) in CH₂Cl₂ (2ml) was added methyl levulinate (0.041 ml, 0.33 mmol, 1.1 equiv)followed by sodium triacetoxyborohydride (0.127 g, 0.6 mmol, 2 equiv.)and the reaction mixture was stirred at 23° C. and stirred for 72 h. Thereaction was quenched with saturated aq. NaHCO₃ (100 ml) and extractedwith EtOAc (200 ml). The organic layer was separated, dried (Na₂SO₄),filtered and concentrated. The mixture was purified by chromatographyover Gilson (1:9, water:CH₃CN) to give the title compound (0.070 g,47%). (Electrospray MS [M+1]⁺ 515.1.

Example 11

Step 1:

Procedures for preparing Compound 14 and Compound 15 are shown in WO01/44200.

Step 2:

To a flask containing ketone Compound 15 (1.05 g, 2.8 mmol, 1 equiv) and(R)-t-butylsulfinamide (0.4 g, 3.3 mmol, 1.8 equiv), was applied avacuum for 5 min. Then, the flask was filled with N₂. Ti(OiPr)₄ (1 ml)was added through a syringe dropwise to the reaction mixture. Thereaction mixture was stirred at 23° C. for 36 h. The reaction mixturewas then poured into brine (10 ml) and EtOAc (20 ml) and stirredvigorously for 10 min. The resulting suspension was passed through a padof celite 545. The celite pad was washed with EtOAc several times. Thecombined organic solution was dried and concentrated under reducedpressure. Flash column chromatography afforded Compound 16 (0.75 g,56%).

Step 3:

To a solution of sulfinimine Compound 16 (2.44 g, 5.1 mmol, 1 equiv) inCH₂Cl₂ at −78° C., was added dropwise allylmagnesium bromide (6.1 ml,6.1 mmol, 1.2 equiv, 1 M in Et₂O) through a syringe. After stirring for3 h at −78° C., the reaction mixture was quenched with a saturatedaqueous NH₄Cl and allowed to warm to 23° C. The layers were separated,and the aqueous layer was extracted with EtOAc. The combined organiclayers were dried and concentrated. Flash column chromatography gaveCompound 17 (1.672 g, 63%).

Step 4:

A 15 ml RBF was charged with Compound 17 (245 mg, 0.47 mmol, 1.0 equiv)and CH₂Cl₂ (2 ml). This pale orange solution was cooled to −78° C., andthen O₃ was bubbled in at 1.0 ml/min. After the solution turned paleblue, the reaction solution was stirred at −78° C. for 10 min. Then itwas flushed with N₂ to get rid of O₃. Tetrabutylammonium iodide (177 mg,0.47 mmol, 1.0 equiv) was added to break the complex. Then it wasquenched with saturated Na₂S₂O₃, and extracted with CH₂Cl₂. The combinedorganic layers were dried, filtered, and concentrated, then re-taken upwith Et₂O and filtered. The residue on the filter was dissolved in waterand extracted with Et₂O. The combined Et₂O layer was dried, filtered andconcentrated to give Compound 18 (243.5 mg, 99%). Electrospray MS [M+1]⁺524.1.

Step 5:

To a solution of Compound 18 (1.2 g, 2.29 mmol, 1.0 equiv)Boc-Phosphonate (818 mg, 2.75 mmol, 1.2 equiv) in DMF (20 ml) was addedCs₂CO₃ (2.24 g, 6.87 mmol, 3.0 equiv). After stirring at RT for 3 h, themixture was diluted with Et₂O, and washed with water (100 ml 2×), andbrine. The combined aqueous layer was further extracted with Et₂O. Thecombined organic layer was dried, filtered and concentrated to givecrude brownish oil, which was purified by column to give Compound 19(830 mg, 55%). Electrospray MS [M+1]⁺ 695.2.

Step 6:

A solution of Compound 19 (830 mg, 1.19 mmol, 1.0 equiv) in EtOH (20 ml)was flushed with N₂. After the addition of Palladium on carbon (10%,1.27 g, 1.19 mmol, 1.0 equiv), a H₂ balloon was attached to the reactionflask. The reaction mixture was stirred for almost 24 h until TLC showedcompletion of the reaction. The mixture was filtered and concentrated togive Compound 20 as white solid (790 mg, 95%). Electrospray MS [M+1]⁺697.2.

Step 7:

A solution of Compound 20 (400 mg, 0.57 mmmol, 1.0 equiv) in anhydrousMeOH (4 ml) was cooled to 0° C., then treated with 4 M solution of HClin 1,4-dioxane (16 ml). After 30 min at 0° C., it was stirred at RT foranother 3 h. The solvent was evaporated under vacuum to give Compound 21as pale brown solid. Electrospray MS [M+1]⁺ 493.1.

Step 8:

To a solution of Compound 21 in MeOH (50 ml) was added K₂CO₃ (4.5 g).The mixture was stirred for 30 min, then filtered and concentrated togive Compound 22 (199 mg, 76%). Electrospray MS [M+1]⁺ 461.1.

Step 9:

A flame-dried 500 ml RBF was charged with ALCl₃ (37.4 mg, 0.28 mmol, 1.5equiv). The reaction flask was cooled to 0° C. and anhydrous THF (1 ml)was syringed in. After stirred for 5 min, 1 M solution of LAH in Et₂O(0.84m1, 0.84 mmol, 4.5 equiv) was cannulated in. The ice-bath wasremoved and the solution was stirred at RT for 30 min. Then the reactionmixture was cooled to −78° C. and a solution of Compound 22 (50 mg,0.187 mmol, 1.0 equiv) in dry THF (1 ml) was slowly added. The reactionmixture was stirred at −78° C., and allowed to warm up to RT overnight.After TLC (MeOH/CH₂Cl₂=1/9) indicated the reaction was completed, thereaction was then cooled to 0° C. and diluted with EtOAc and quenchedcarefully with saturated aqueous sodium potassium tartarate solution. Itwas stirred at RT for over 30 min to get separation of the two layers.The aqueous layer was further extracted with EtOAc. The combined organiclayer was dried over Na₂SO₄, filtered and concentrated to give Example11 (34 mg, 41%). Electrospray MS [M+1]⁺ 447.1.

Example 12a and Example 12b

Step 1:

To a solution of Example 11 (30 mg, 0.067 mmol, 1.0 equiv) in CH₂Cl₂ (10ml) at 0° C. was added DIEA(17.5 μl, 0.10 mmol, 1.5 equiv) and Ac₂O (6.3μl, 0.067 mmol, 1.0 equiv). The mixture was stirred at 0° C. for 30 min.It was quenched with saturated aqueous NaHCO₃ solution (4 ml) andextracted with CH₂Cl₂. The combined organic layers were dried, filteredand concentrated to give the crude product (39 mg). Purification of themixture by HPLC using ChiralPak AD column (2:98, IPA:hexane) gave morepolar isomer Example 12a, Electrospray MS [M+1]⁺ 489.1, and less polarisomer Example 12b, Electrospray MS [M+1]⁺ 489.1.

Example 13

Step 1:

To a suspension of (methoxymethyl)triphenylphosphonium chloride (21.3 g,0.062 mmol, 2.95 equiv) in toluene (300 ml) at 0° C. under N₂, asolution of potassium bis(trimethylsilyl)amide (125 ml, 0.062 mmol, 2.95equiv) was added. After being stirred at 0° C. for 1 h, a solution ofCompound 3 (13.4 g, 0.021 mmol, 1 equiv) in toluene (100 ml) was added.The mixture was allowed to stir from 0° C. to 23° C. in 1 h and then wasquenched with saturated NH₄Cl solution. Et₂O was added and layers wereseparated. The separated aqueous layer was extracted with Et₂O (400ml×2). The combined organic layers were dried (MgSO₄) and filtered.Solvents were removed in vacuum to give crude enol ether as yellow oil.

The crude enol ether was dissolved in THF (100 ml) at 23° C. and aqueousHCl (100 ml, 10% in water) was added. The mixture was stirred overnightand was quenched with saturated KHCO₃ solution. Et₂O was added andlayers were separated. The separated aqueous layer was extracted withEt₂O (300 ml×2). The combined organic layers were dried (MgSO₄) andfiltered. Removal of solvents in vacuum followed by chromatographicpurification [hexane:EtOAc, 4:1 (v/v)] gave Compound 23 (6.97 g, 61 %)as yellow oil.

Step 2:

Compound 24 was prepared from Compound 23 using a procedure similar tothe preparation of Compound 4 from Compound 3 and usingPO(OEt)₂CH(NHCbz)CO₂Me in place of PO(OMe)₂CH(NHBoc)CO₂Me.

Step 3:

Compound 25 was prepared using a procedure similar to that for Compound9 using Compound 24 instead of Compound 7. Electrospray MS [M+1]⁺ 461.1.

Step 4:

Example 13 (6.84 g, 73%) was prepared using similar procedure toCompound 6 using Compound 25 instead of Compound 5.

Electrospray MS [M+1]⁺ 447.1.

Example 14

To a solution of Example 13 (275 mg, 0.60 mmol, 1.0 equiv) in anhydrousCH₂Cl₂ (10 ml) at −78° C. was added propionyl chloride (52 μl, 0.60mmol, 1.0 equiv). The reaction was completed within 30 min. Reactionmixture was quenched with 7N ammonia in MeOH (0.5 ml), then loadeddirectly onto silica column and purified to give Example 14. (241.3 mg,80%). Electrospray MS [M+1]⁺ 503.1.

Example 15

Example 15 (yield 89%) was prepared using similar procedure as forExample 14 using cyclopropanecarbonyl chloride in place of propionylchloride.

Electrospray MS [M+1]⁺ 515.1.

Example 16

Example 16 (yield 89%) was prepared using similar procedure as forExample 14 using Example 13 and CH₃SO₂Cl in place of propionyl chloride.

Electrospray MS [M+1]⁺ 52.1.

Example 17

Example 17 (overall yield 23%) was prepared using similar procedure asfor Example 3 using Example 13 in place of Compound 10.

Electrospray MS [M+1]⁺ 515.1.

Example 18

Example 18 (overall yield 42%) was prepared using similar procedure asfor Example 4 using Example 13 in place of Compound 10.

Electrospray MS [M+1]⁺ 529.1.

Preparation of Compounds 26, 27, 28 and 29:

Compound 26 was prepared from Compound 1 using similar procedure as forCompound 9.

Compound 27 was prepared using similar procedure as for Compound 10.

Compound 28 (90% yield) was prepared using the similar procedure forCompound 25. Electrospray MS [M+1]⁺ 447.1.

Compound 29 was prepared using similar procedure as for Example 13.

Electrospray MS [M+1]⁺ 433.1.

Example 19

Example 19 (40 mg, 70% yield) was prepared using a procedure similar toExample 1a using Compound 27 instead of Compound 6.

Electrospray MS [M+1]⁺ 461.1.

Example 20

Example 20 (99 mg, 72%) was prepared using similar procedure as forExample 1a using Compound 29 instead of Compound 6.

Electrospray MS [M+1]⁺ 475.1.

Example 21

Example 21 (74 mg, 66%) was prepared from Compound 29 using similarprocedure as for Example 2 from Compound 10 using propionic anhydride inplace of cyclopropanecarbonyl chloride. Electrospray MS [M+1]⁺ 489.1.

Example 22

Example 22 (75 mg, 78%) was prepared from Compound 29 using similarprocedure as for Example 2 from Compound 10 using isobutyryl chloride inplace of cyclopropanecarbonyl chloride. Electrospray MS [M+1]⁺ 503.1.

Example 23

Example 23 (9 mg, 35%) was prepared from Compound 29 using similarprocedure as for Example 2 from Compound 10. Electrospray MS [M+1]⁺501.1.

Example 24

Example 24 (31 mg, 71 %) was prepared from Compound 29 using similarprocedure as for Example 3 from Compound 10. Electrospray MS [M+1]⁺501.1.

Example 25

Example 25 (68 mg, 68%) was prepared from Compound 29 using similarprocedure as for Example 4 from Compound 10. Electrospray MS [M+1]⁺515.1.

Example 26

To a solution of Example 13 (0.14 g, 0.314 mmol, 1 equiv) in anhydrousDMF (1.6 ml) at 23° C. was added N,N-dimethyl glycine (33.95 mg, 0.329mmol, 1.05 equiv) followed by EDC.HCl (66.13 mg, 0.345 mmol, 1.1 equiv)and the reaction mixture was stirred at 23° C. for 18 h. The reactionmixture was diluted with DMF (2.4 ml) and purified using Gilson to giveExample 26 (66 mg, 40%). Electrospray MS [M+1]⁺ 532.1.

Example 27

Example 27 (yield 62%) was prepared using similar procedure as forExample 14 using trimethylacetyl chloride in place of propionylchloride.

Electrospray MS [M+1]⁺ 531.1

Example 28

Example 28 (105 mg, 74%) was prepared using similar procedure as forExample 14 using methyl isocyanate in place of propionyl chloride.

Electrospray MS [M+1]⁺ 504.1

Example 29

Example 29 (146 mg, 754%) was prepared using similar procedure as forExample 14 using trimethylsilyl isocyanate in place of propionylchloride.

Electrospray MS [M+1]⁺ 490.1

Example 30

To a solution of Example 13 (100 mg, 0.224 mmol, 1 equiv) in anhydrousCH₂Cl₂ (2 ml) was added 4-morpholinylcarbonyl chloride (28.7 μl, 0.246mmol, 1.1 equiv) and DIEA (39 μl, 0.223 mmol, 1 equiv). The reactionmixture was stirred at RT overnight. Aqueous work-up and purification byusing silica column to afford Example 30 (53 mg, 42%). Electrospray MS[M+1]⁺ 560.1

Example 31

Example 31 (40% yield) was prepared using similar procedure as forExample 30 using dimethylcarbamyl chloride in place of4-morpholinylcarbonyl chloride. Electrospray MS [M+1]⁺ 518.1

Example 32

Example 32 (42% yield) was prepared using similar procedure as forExample 30 using 1-piperidinecarbonyl chloride in place of4-morpholinylcarbonyl chloride. Electrospray MS [M+1]⁺ 558.1

Example 33

Example 33 (40% yield) was prepared using similar procedure as forExample 30 using 1-pyrrolidinecarbonyl chloride in place of4-morpholinylcarbonyl chloride. Electrospray MS [M+1]⁺ 544.1

Example 34

Step 1:

Compound 30 (43% yield) was prepared using similar procedure as forExample 10 using chloroacetyl chloride in place of propionyl chloride.

Step 2:

To a solution of Compound 30 (90 mg, 0.17 mmol, 1 equiv) in anhydrousCH₂Cl₂ (0.5 ml) was added pyrrolidine (1 7.2 μl, 0.206 mmol, 1.2 equiv)and DIEA (30 μl, 0.17 mmol, 1 equiv). The reaction mixture was stirredat RT overnight. Aqueous work-up and purification by using silica columnto afford Example 34 (45 mg, 47%).

Electrospray MS [M+1]⁺ 558.1.

Example 35 Example 36

Step 1:

Compound 31 was prepared using similar procedure as for Example 14 using2-chloroethyl isocyanate in place of propionyl chloride.

Step 2:

To a solution of Compound 31 in anhydrous THF (7 ml), was added NaH (25mg, 0.625 mmol, 1.7 equiv, 60% dispersion in mineral oil) at 0° C. Theresulting cloudy solution was heated at 60° C. for 2 h. Aqueous work-upto give the crude product which was purified by silica gel column togive the less polar title compound Example 35 (10 mg, 5.4%),Electrospray MS [M+1]⁺ 516.1; and the more polar title compound Example36 (122 mg, 66%), Electrospray MS [M+1]⁺ 516.1

Example 37

To a solution of Example 12b (200 mg, 0.41 mmol, 1 equiv) in anhydrousCH₂Cl₂ (1 ml) at 0° C., was added trifluoromethanesulfonic anhydride (69μl, 0.41 mmol, 1 equiv). The reaction mixture was stirred for 40 minbefore NaN₃ (26.6 mg, 0.41 mmol, 1 equiv) was added. The mixture waswarmed up to RT for 2 h. The solvent was removed in vacuum. The residuewas purified with prep-TLC (silica) to obtain Example 37 (4.5 mg, 2%).Electrospray MS [M+1]⁺ 514.1

Example 38

Step 1:

To Compound 17 (0.3 g, 0.575 mmol, 1 equiv) under N₂ in anhydrous DMF (3ml) at 0° C. was added NaH (27.6 mg, 0.69 mmol, 1.2 equiv, 60% inmineral oil) and the reaction mixture was stirred for 1 h. To theresulting suspension under vigorous stirring was dropwise addedethyl-2-bromomethylacrylate (0.088 ml, 0.629 mmol, 1.1 equiv). Thereaction mixture was allowed to warm to 23° C. and stirred for 18 h. Thereaction was quenched with saturated aqueous NH₄Cl solution andextracted with Et₂O. The combined organic layers were washed with water,brine, dried over Na₂SO₄ and concentrated. The crude product waspurified using flash silica gel column to give titled Compound 32 (0.199g, 55%).

Step 2:

To a solution of Compound 32 (50 mg, 0.078 mmol, 1 equiv) in anhydrousCH₂Cl₂ (0.8 ml) under N₂ was added Grubbs' catalysttricyclohexylphosphine[1,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydro-imidazol-2-ylidene][benzylidine]ruthenium(IV)dichloride (6.7 mg, 0.0079 mmol, 0.1 equiv). The resulting brownsolution was heated at 40-45° C. for 2 h. The solvent was then removedand the residue was purified on a silica gel column to afford the titledCompound 33-(60 mg, 63%). Electrospray MS [M+1]⁺ 502.1.

Step 3:

To a solution of Compound 33 (30 mg, 0.05 mmol, 1 equiv) in absoluteMeOH (0.5 ml) at 0° C. was added a solution of 4N HCl in dioxane (0.5ml). The resulting solution was stirred at 0° C. for 4 h. The solventwas then removed and the residue was dissolved in CH₂Cl₂ and passedthrough a short K₂CO₃ column. The residue of Compound 34 was takendirectly to the next step without further purification.

Step 4:

A solution of Compound 34 (30 mg, 0.06 mmol) in EtOH (5 ml) was treatedwith 10% Pd—C (32 mg, 0.03 mmol) and was hydrogenated at 60 psig for 18h. The catalyst was filtered and washed with EtOAc. The filtrate wasconcentrated and the resulting residue of Compound 35 was taken directlyto the next step without further purification.

Step 5:

To a mixture of methylamine HCl salt (52 mg, 0.77 mmol, 12.8 equiv) intoluene (0.2 ml) was added Me₃Al (2M in toluene, 0.36 ml, 0.72 mmol) andthe resulting mixture stirred for 30 min. A solution of Compound 35 (30mg, 0.06 mmol) in toluene (0.5 ml) was added to the reaction mixture viasyringe. The resulting solution was heated at 100° C. for 18 h. Thereaction mixture was then poured into saturated aq. Na/K tartaratesolution (10 ml), stirred for 10 min and extracted with EtOAc (4×10 ml).The combined organic layers were-washed with brine and concentrated. Theresidue was subjected to prep TLC to afford the less polar isomer,Example 38a, Electrospray MS [M+1]⁺ 489.1 and the more polar isomer,Example 38b, Electrospray MS [M+1]⁺ 489.1.

Example 39

Step 1:

Compound 36 (yield 63%) was prepared from Compound 23 using theprocedure similar to the preparation of Compound 23 from Compound 3 andusing methyltriphenyl-phosphonium bromide in place of(methoxymethyl)triphenylphosphonium chloride.

Step 2:

Compound 37 (50% yield) was prepared using similar procedure as forCompound 32 using Compound 36 in place-of Compound 17.

Step 3:

To a solution of Compound 37 (2.46 g, 3.71 mmol, 1 equiv) in anhydrousCH₂Cl₂ (50 ml) under N₂ was added Grubbs' catalyst (327 mg, 0.385 mmol,0.1 equiv). The resulting brown solution was heated at 40-45° C.overnight. The solvent was then removed and the residue was purified ona silica gel column to afford Compound 38 (2.1 g, 89%).

Step 4:

To a mixture of cyclopropylamine (0.24 ml, 3.45 mmol, 4.2 equiv) intoluene (1.0 ml) was added Me3Al (2M in toluene, 1.71 ml, 3.41 mmol, 4.2equiv) and the resulting mixture stirred for 30 min. A solution ofCompound 38 (516 mg, 0.82 mmol, 1 equiv) in toluene (2.5 ml) was addedto the reaction mixture via syringe. The resulting solution was heatedat 60° C. for 18 h. The reaction mixture was then poured into saturatedaq. Na,K tartarate solution, stirred for 10 min and extracted with EtOAc(10 ml×4). The combined organic layers were washed with brine andconcentrated. The residue was purified on silica column to affordCompound 39 (360 mg, 68%).

Step 5:

A solution of Compound 39 (360 mg, 0.556 mmol, 1 equiv) in EtOH (25 ml)was treated with 10% Pd—C (641 mg, 0.613 mmol, 1.1 equiv) and washydrogenated at 50 psi for 6 h. The catalyst was filtered and washedwith EtOAc. The residue was purified by silica gel column to afford theless polar isomer, Example 39a (54 mg, 19%) Electrospray MS [M+1]⁺515.1, and the more polar isomer, Example 39b (22 mg, 8%) ElectrosprayMS [M+1]⁺ 515.1

Example 40a and Example 40b

Step 1:

Compound 40 (yield 55%) was prepared using similar procedure as forCompound 39 using para-methoxylbenzylamine in place of cyclopropylamine.

Step 2:

A solution of Compound 40 (1 g, 1.38 mmol, 1 equiv) in CH₃CN (10 ml) andpH7 buffer (3 ml) was treated with ammonium cerium(IV) nitrate (2.17 g,3.96 mmol, 2.9 equiv) at RT for 2 h. Aqueous work-up gave the crudeproduct which was purified by silica gel column to give Compound 41 (760mg, 91%).

Step 3:

Example 40a and Example 40b were prepared using a similar procedure asfor Example 39a and Example 39b using Compound 41 instead of Compound39.

Electrospray MS [M+1]⁺ 475.1 for the Example 40a (less polar isomer);

Electrospray MS [M+1]⁺ 475.1 for the Example 40b (more polar isomer).

Example 41

Example 41a and Example 41b were prepared using a similar procedure asfor Example 38a and Example 38b using ethylamine instead of methylamine.

Electrospray MS [M+1]⁺ 503.1 for the Example 41a (less polar isomer);

Electrospray MS [M+1]⁺ 503.1 for the Example 41 b (more polar isomer).

Example 42

The mixture of two isomers of Compound 35 was separated by columnchromatography to give pure Example 42a and Example 42b

Electrospray MS [M+1]⁺ 504.1 for the Example 42a (less polar isomer);

Electrospray MS [M+1]⁺ 504.1 for the Example 42b (more polar isomer).

Example 43a Example 43b

Step 1:

To a suspension of lactol Compound 3 (60 g, 93.0 mmol, 1 equiv.) andWittig Reagent (93.5 g, 200.0 mmol, 2.15 equiv.) in toluene (800 ml)stirred at −78° C. under N₂, a solution of KHMDS (0.5M in toluene, 558ml, 280.0 mmol, 3 equiv.) was added dropwise at −78° C. The cooling bathwas removed and the yellow mixture was warmed to RT to form a redsolution. The mixture was allowed to stir at 23° C. for further 1 hbefore being quenched with saturated NH₄Cl solution. EtOAc was added andlayers were separated. The separated aqueous layer was extracted withEtOAc (2×500 ml). The combined organic layers were dried (MgSO₄) andfiltered. Removal of solvents in vacuum followed by Biotage columnchromatography [5% EtOAc-hexane to 10% EtOAc-hexane] gave alkeneCompound 42 as white solid (40.5 g, 68%), Electrospray MS [M+1]⁺ 638.1.Continuous elution gave an impure cyclized product Compound 43.

Step 2:

A suspension of alkene Compound 42 (40.5 g, 64 mmol, 1 equiv.) and PtO₂(1.44 g, 6.4 mmol, 0.1 equiv.) in EtOH (400 ml) were stirred under a H₂balloon at 23° C. for 24 h. Another batch of PtO₂ (1.44 g, 6.4 mmol, 0.1equiv) was added and the mixture was stirred for another 24 h at 23° C.The catalyst was filtered via a pad of Celite. This solution of alkaneCompound 44 was used in the next step without further purification.

Step 3:

p-TsOH.H₂O (2.42 g, 13.0 mmol) was added to the ethanolic solution ofalkane Compound 44 from above and the solution was heated to reflux for4 h. The solution was cooled to RT and neutralized with Et₃N. Solventswere removed in vacuum and EtOAc was added. Saturated NaHCO₃ solutionwas added and layers were separated. The separated aqueous layer wasextracted with EtOAc (300 ml×2). The combined organic layers were dried(MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotagecolumn chromatography [10% ether-hexane] gave enamide Compound 45 (firstbatch) as yellow oil. Some intermediate and starting material wererecovered as yellow oil by continuous elution with [50% EtOAc-hexane].The yellow oil was dissolved in toluene and 10 mol % p-TsOH was added.The mixture was heated to reflux for 2 h and cooled to RT. Work up wasas above and the combined enamide Compound 45 (25 g, 70%), ElectrosprayMS [M+1]⁺ 564.1, was obtained as yellow oil.

Step 4:

BH₃.Me₂S (13.6 ml, 133 mmo, 3.02 equiv) was added to a solution ofenamide Compound 45 (25 g, 44.0 mmol,1 equiv.) in THF at 23° C. underN₂. The mixture was stirred at 23° C. for 18 h and then cooled over anice-water bath. A solution of NaOH (500 ml, 2N) was added slowlyfollowed by a solution of H₂0₂ (500 ml, 30% aqueous). The mixture wasallowed to stir from 0° C. to 23° C. for 18 h. Layers were separated andthe separated aqueous layer was extracted with Et₂O (500 ml×2). Thecombined organic layers were dried (MgSO₄) and filtered. Removal ofsolvents in vacuum followed by Biotage column chromatography[hexane-EtOAc, 3:1 (v/v)] gave alcohol Compound 46 as colorless oil (19g, 74%), Electrospray MS [M+1]⁺ 582.1.

Step 5:

Oxalyl chloride (5.7 ml, 65.3 mmol, 2 equiv.) was added to a solution ofDMSO (9.3 ml, 131.0 mmol, 4 equiv.) in CH₂Cl₂ (300 ml) at −78° C. underN₂. The mixture was stirred at −78° C. for 15 min before a solution ofalcohol Compound 46 (19 g, 32.7 mmol. 1 equiv.) in CH₂Cl₂ (50 ml) wasadded. The mixture was stirred at −78° C. for a further 1 h and Et₃N (32ml, 228.9 mmol, 7 equiv.) was added. The cooling bath was removed andthe mixture was warmed to RT before it was quenched with saturatedNaHCO₃ solution. Layers were separated and the aqueous was extractedwith CH₂Cl₂ (300 ml×2). The combined organic layers were dried (MgSO₄)and filtered. Removal of solvents in vacuum followed by Biotage columnchromatography [hexane-ether, 4:1 (v/v)] gave ketone Compound 47 ascolorless oil (15 g, 80%), Electrospray MS [M+1]⁺ 580.1.

Step 6:

EtOH (150 ml) was added to Cbz-ketone Compound 47 (15 g, 25.88 mmol, 1equiv.), followed by NH₄(CO₃)₂ (9.95 g, 103.5 mmol, 4 equiv.) and asolution of KCN (3.4 g, 51.77 mmol, 2 equiv.). The resulting mixture washeated at 58° C. under N₂ for 72 h. TLC (1:1 EtOAc:hexane) revealedcomplete consumption of the starting material. The reaction mixture wascooled to RT and poured into sat. aq. NaHCO₃ (200 ml) and extracted withEtOAc (3×200 ml). The combined organic layers were dried over MgSO₄ andconcentrated in vacuo to afford crude Cbz-hydantoin Compound 48 (16.5 g,98%), Electrospray MS [M+1]⁺650.1. The crude material was used in thenext reaction without further purification.

Step 7:

The crude Cbz-hydantoin Compound 48 (16.5 g, 25.4 mmol, 1 equiv.) wasdissolved in MeOH (220 ml) and 20% Pd(OH)₂—C (3.6 g) was added. Thereaction mixture was shaken in a parr shaker under H₂ atmosphere at 40psi for 18 h. TLC (1:1 EtOAc:hexane) revealed complete consumption ofthe starting material. The reaction mixture was filtered through a padof celite and the celite was washed with MeOH. The resulting solutionwas concentrated in vacuo. The crude product was purified by columnchromatography on a Biotage (3:2, EtOAc:hex). Two major spots werecollected. The less-polar spot corresponds to the isomer Example 43a (3g, overall 20% over two steps), Electrospray MS [M+1]⁺ 516.1. The morepolar spot corresponds to the isomer Example 43b (4.5 g, overall 30%over two steps), Electrospray MS [M+1]⁺ 516.1.

Examples 44a and 44b

A flame-dried 25 ml RBF was charged with AlCl₃ (0.01 g, 0.776 mmol, 4equiv). The reaction flask was cooled to 0° C. and 1 M solution of LAHin Et₂O (0.58 ml, 0.58 mmol, 3 equiv) was added. The mixture was stirredat 0° C. for 10 min and then a solution of Example 43b (0.1 g, 0.194mmol, 1 equiv.) in dry THF (3 ml) was slowly added via cannula. Thereaction mixture was stirred at 0° C. for 1 h and then allowed to warmup to RT stirred for 18 h. The reaction was then cooled to 0° C. andquenched carefully with saturated aqueous sodium potassium tartaratesolution. It was then stirred at 0° C. for over 30 min. The mixture wasextracted with EtOAc (2×200 ml). The combined organic layer was driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby column chromatography on a Biotage (1:9, MeOH:EtOAc) to affordExample 44b (0.066 g, 68%), Electrospray MS [M+1]⁺ 502.1.

Example 44a was prepared from Example 43a using the procedure describedfor the preparation of Example 44b from Example 43b.

Electrospray MS [M+1]⁺ 502.1 for the Example 44a.

Example 45

Step 1:

To a suspension of (methyl)triphenylphosphonium bromide (0.37 g, 1.04mmol, 3 equiv) in toluene (5 ml) at 0° C. under N₂, a solution of KHMDS(1.73 ml, 0.863 mmol, 2.5 equiv) was added. After being stirred at 0° C.for 1 h, a solution of Compound 47 (0.2 g, 0.35 mmol, 1 equiv) intoluene (7 ml) was added. The mixture was stirred at 0° C. for 1.5 h andthen quenched with saturated NaHCO₃ (150 ml). The mixture was extractedwith EtOAc (100 ml×3). The combined organic layers were dried (MgSO₄),filtered and concentrated. The crude product was purified by columnchromatography on a Biotage (4:1, hexane:EtOAc) to afford Compound 49(0.196 g, 98%).

Step 2:

To a solution of Compound 49 (0.196 g, 0.34 mmol, 1 equiv) in dry Et₂O(3 ml) at 0° C. was added chlorosulfonylisocyanate (0.045 ml, 0.51 mmol,1.5 equiv). The reaction mixture was stirred at 0° C. for 1 h and thenwarmed to 23° C. Another equivalent of chlorosulfonylisocyanate wasadded and the mixture was stirred 23° C. for 18 h. The reaction mixturewas diluted with Et₂O (12 ml), 10% aqueous Na₂SO₃ solution was added andpH of the reaction mixture was adjusted to 8 using 2M aqueous KOHsolution. The mixture was stirred for 1.5 h and then washed with brine.The organic layer was dried (MgSO₄), filtered and concentrated. Thecrude product was purified by column chromatography on a Biotage (2:1,hexane:EtOAc) to afford the crude NCbz-lactam product (20 mg) which wasconverted to mixture of desired products Example 45a and 45b using aprocedure similar to the preparation of Example 43a and Example 43b fromCompound 48. The mixture of two products was separated on prep. plate(6:95, MeOH;EtOAc) to afford the less polar isomer, Example 45a (0.006g, 3.5% over four steps), Electrospray MS [M+1]⁺ 487.1 and the morepolar isomer, Example 45b (0.003 g, 1.79% over four steps), ElectrosprayMS [M+1]⁺ 487.1.

Examples 46

Example 46a and Example 46b were prepared from Compound 46 using aprocedure similar to the preparation of Example 43a and Example 43b fromCompound 48.

Electrospray MS [M+1]⁺ 448.1 for the Example 46a (less polar isomer);

Electrospray MS [M+1]⁺ 448.1 for the Example 46b (more polar isomer).

Example 47

To a solution of NCbz-alcohol Compound 46 (0.125 g, 0.215 mmol, 1 equiv)in dry DMF (3 ml) at 0° C. was added NaH (60% in mineral oil, 0.017 g,0.43 mmol, 2 equiv). The reaction mixture was stirred at 0° C. for 20min and then CH₃I (0.04 ml, 0.645 mmol, 3 equiv) added and the mixturewas stirred at 23° C. for 18 h. The crude was poured into CH₂Cl₂ (100ml) and washed with brine (100 ml×2). The organic layer was dried(MgSO₄), filtered and concentrated. The crude product was purified bycolumn chromatography over Biotage (4:1, hexane:EtOAc) to afford thecrude NCbz-methylether product (69 mg) which was hydrogenated to themixture of desired products Example 47a and 47b using a proceduresimilar to the preparation of Example 43a and Example 43b from Compound48. The mixture of two products was purified by column chromatographyover Biotage (1:4, hexane:EtOAc) to afford the less polar isomer,Example 47a, Electrospray MS [M+1]⁺ 462.1 and the more polar isomer,Example 47b, Electrospray MS [M+1]⁺ 462.1.

Example 48

Example 48a and Example 48b were prepared from Compound 46 using theprocedure similar to the preparation of Example 47a and Example 47b andusing ethyl iodide in place of methyl iodide.

Electrospray MS [M+1]⁺ 476.1 for the Example 48a (less polar isomer);

Electrospray MS [M+1]⁺ 476.1 for the Example 48b (more polar isomer)

Example 49

To a solution of NCbz-alcohol Compound 46 (0.118 g, 0.20 mmol, 1 equiv)in dry CH₂Cl₂ (3 ml) at 0° C. was added dry pyridine (0.026 ml, 0.325mmol, 1.6 equiv), followed by acetyl chloride (0.023 ml, 0.325 mmol, 1.6equiv). The reaction mixture was warmed to 23° C. for and stirred for 18h. The mixture was then concentrated and purified by columnchromatography on a Biotage (4:1, hexane:EtOAc) to afford the crudeNCbz-acetate product (108 mg) which was hydrogenated to the crudedesired product using a procedure similar to the preparation of Example23a and Example 23b from Compound 48. The crude product was purified bycolumn chromatography on a Biotage (5:95 MeOH:EtOAc) to afford Example49 (0.079 g, 79% over two steps), Electrospray MS [M+1]⁺ 490.1.

Examples 50a and 50b

To a solution of NCbz-alcohol Compound 46 (0.223 g, 0.385 mmol, 1 equiv)in CH₂Cl₂ (8 ml) at 0° C. was added trichloroacetyl isocyanate (0.055ml, 0.46 mmol, 1.2 equiv). The reaction mixture was stirred at 0° C. for15 min and then concentrated in vacuo. The residue was dissolved inCH₃OH (7 ml) and water (5 ml) was added. The mixture was cooled to 0° C.and K₂CO₃ (0.16 g, 1.16 mmol, 3 equiv) was added. The reaction mixturewas stirred at 0° C. for 1 h and then warmed to 23° C. and stirred for18 h. The reaction mixture was then concentrated in vacuo and water (100ml) was added to the residue and the mixture was extracted with CH₂Cl₂(1 00 ml×2). The combined organic layers were dried (Na₂SO₄), filteredand concentrated to afford the crude NCbz-carbamate product (232 mg)which was hydrogenated to the mixture of desired products Example 50aand 50b using a procedure similar to the preparation of Example 43a andExample 43b from Compound 48. The mixture of two products was purifiedby column chromatography over Biotage (1:4, hexane:EtOAc) to afford pureExample 50a and pure Example 50b.

Electrospray MS [M+1]⁺ 491.1 for the Example 50a (less polar isomer);

Electrospray MS [M+1]⁺ 491.1 for the Example 50b (more polar isomer)

Example 51

A mixture of NCbz-alcohol Compound 46 (0.2 g, 0.344 mmol, 1 equiv.),1,4-dioxane (3 ml), 1-pyrrolidine carbonyl chloride (0.076 ml, 0.69mmol, 2 equiv.) and dry pyridine (0.084 ml, 1.03 mmol, 3 equiv.) washeated in a sealed tube at 100° C. for 18 h. The reaction mixture wascooled to 23° C. and diluted with EtOAc (150 ml). The mixture was washedwith water (1 00 ml) and the organic layer was dried (Na₂SO₄), filteredand concentrated to afford the crude NCbz-carbamate product (232 mg)which was hydrogenated to the mixture of desired products Example 51aand 51b using a procedure similar to the preparation of Example 43a andExample 43b from Compound 48. The mixture of two products was purifiedby column chromatography over Biotage (2:3, hexane:EtOAc) to afford theless polar isomer, Example 51a and the more polar isomer, Example 51b.

Electrospray MS [M+1]⁺ 545.1 for the Example 51a;

Electrospray MS [M+1]⁺ 545.1 for the Example 51b.

Example 52

Example 52a and Example 52b were prepared from Compound 46 using theprocedure similar to that used for the preparation of Example 51a andExample 51b and using 1-piperidine carbonyl chloride in place of1-pyrrolidine carbonyl chloride.

Electrospray MS [M+1]⁺ 559.1 for the Example 52a (less polar isomer);

Electrospray MS [M+1]⁺ 559.1 for the Example 52b (more polar isomer).

Example 53

Example 53a and Example 53b were prepared from Compound 46 using theprocedure similar to that used for the preparation of Example 51a andExample 51 b and using methylisocyanate in place of 1-pyrrolidinecarbonyl chloride.

Electrospray MS [M+1]⁺ 505.1 for the Example 53a (less polar isomer);

Electrospray MS [M+1]⁺ 505.1 for the Example 53b (more polar isomer).

Example 54

CeCl₃ (0.186 g, 0.5 mmol, 2.1 equiv) was added to a 25 ml RBF and heatedin vacuo at 140° C. for two h. The flask was cooled to 23° C. under N₂,dry THF (2 ml) was added and the resulting suspension was stirred at 23°C. for 18 h. The mixture was then cooled to 140° C. and CH₃Mgl (0.159ml, 0.476 mmol, 2 equiv.) was added and stirred at 0° C. for 1 h. Asolution of Compound 47 (0.138 g, 0.238 mmol, 1 equiv) in dry THF (2.5ml) was added dropwise and the reaction mixture was stirred under N₂ at0° C. for 0.5 h. The mixture was quenched with saturated aq. NH₄Clsolution (50 ml) and extracted with EtOAc (100 ml×2). The combinedorganic layers were dried (MgSO₄), filtered and concentrated. Themixture was purified by column chromatography over Biotage (4:1,hexane:Et₂O) to afford the NCbz-alcohol Compound 50 (0.115 g, 80%).

The NCbz-alcohol Compound 50 was converted to the desired productExample 54 (63% yield over two steps) using a procedure similar to thepreparation of Example 49 from Compound 46.

Electrospray MS [M+1]⁺ 504.1 for the Example 54.

Example 55

To a solution of Compound 47 (0.1 g, 0.173 mmol, 1 equiv) in drypyridine (1 ml) was added methoxylamine hydrochloride (0.058 g, 0.69mmol, 4 equiv) and the reaction mixture was stirred 23° C. for 18 h. Themixture was quenched with water (50 ml) and extracted with CH₂Cl₂ (100ml×2). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated to give NCbz-oxime (0.102 g, 97%) which was hydrogenated toafford the crude product Example 55 using a procedure similar to thepreparation of Example 43a and Example 43b from Compound 48, except thatthe reaction was carried out in a H₂ balloon atmosphere at RT instead ofa parr shaker at 40 psi. The crude product was purified by columnchromatography over Biotage (4:1, EtOAc:hexane) to afford Example 55(0.063 g, 79%), Electrospray MS [M+1]⁺ 475.1.

Examples 56a and 56b

Step 1:

To a suspension of NaH (1.8 g, 44.5 mmol, 60% in oil) in THF (200 ml) at0° C. under N₂, methyl diethylphosphonoacetate (8.2 ml, 44.5 mmol) wasadded. The mixture was stirred at 0° C. for 15 min and a solution ofketone Compound 47 (8.6 g, 14.8 mol) in THF (50 ml) was added. Themixture was allowed to warm to RT and stirred for 1 h before it wasquenched with saturated NH₄Cl solution. Water and EtOAc were added tothe mixture. Layers were separated and the aqueous layer was extractedwith EtOAc (200 ml×2). The combined organic layers were dried (MgSO₄)and filtered. Solvents were removed in vacuum and purification by columnchromatography [hexane-EtOAc, 4:1 (v/v)] gave unsaturated ester Compound51 (9.2 g, 98%) as colorless oil. Electrospray MS [M+1]⁺=636.1.

Step 2:

A mixture of unsaturated ester Compound 51 (9.2 g, 14.5 mmol) andtetrabutylammonium fluoride (145 ml, 1.0 M in THF) in CH₃NO₂ were heatedto reflux for 2 h. The mixture was cooled to RT and quenched withsaturated NH₄Cl solution. Water and EtOAc were added to the mixture.Layers were separated and the aqueous layer was extracted with EtOAc(X2). The combined organic layers were dried (MgSO₄) and filtered.Solvents were removed in vacuum and purification by columnchromatography [hexane-acetone, 9:1 (v/v)] gave the less polar alkene(4.1 g, 45%) as colorless oil. Continuous elution with the same solventsystem gave the more polar nitroester Compound 52 (5.1 g, 50%) ascolorless oil. Electrospray MS [M+1]⁺=670.1.

Step 3:

A mixture of Compound 52 (5.1 g, 7.32 mmol), a catalytic amount ofPd(OH)₂ (20% on carbon) and a catalytic amount of Raney Ni (50% slurryin water) were shaken in a Parr hydrogenator at 50 psi overnight. Themixture was filtered through a pad of Celite and solvents were removedin vacuum to give a mixture of Example 56a and 56b as colorless oil (3.5g, 95%). Separation by HPLC using Chiralcel OD [hexane-isopropanol, 9:1(v/v)] gave less polar isomer Example 56a as white foam. Electrospray MS[M+1]⁺=501.1. Continuous elution with the same solvent system gave themore polar isomer Example 56b as colorless oil. Electrospray MS[M+1]⁺=501.1.

Example 57

To a solution of ethyl propiolate (0.27 ml, 2.69 mmol) in THF (10 ml) at−78° C. under N₂, t-butyllithium (1.6 ml, 2.69 mmol, 1.7M in pentane)was added. The mixture was stirred at −78° C. for 10 min and a solutionof Compound 47 (519 mg, 0.90 mmol) in THF (5 ml) was added. The mixturewas stirred at −78° C. for 1 h, then quenched with HOAc at −78° C. Waterand EtOAc were added to the mixture. Layers were separated and theaqueous layer was extracted with EtOAc (200 ml×2). The combined organiclayers were dried (MgSO₄) and filtered. Solvents were removed in vacuumand purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gavea colorless oil. The oil was dissolved in EtOH and a catalytic amount ofpalladium (10% on carbon) was added. The mixture was shaken in a Parrhydrogenator at 45 psi overnight. The mixture was filtered through a padof Celite and solvents were removed in vacuum to give a colorless oil.The oil was dissolved in toluene and catalytic amount of p-TsOH wasadded. The mixture was heat to reflux overnight. After being cooled toRT, the mixture was quenched with saturated NaHCO₃ solution. Water andEtOAc were added to the mixture. Layers were separated and the aqueouslayer was extracted with EtOAc (250 ml×2). The combined organic layerswere dried (MgSO₄) and filtered. Solvents were removed in vacuum to givea mixture of Example 57a and 57b as colorless oil. Separation by columnchromatography [hexane-ether, 1:2(v/v)] gave the less polar minor isomerExample 57a (67 mg, 15%) as white foam. Electrospray MS [M+1]⁺=502.1.Continuous elution with the same solvent system gave the more polarmajor isomer Example 57b (134 mg, 30%) as white solid. Electrospray MS[M+1]⁺=502.1.

Example 58

To a solution of Example 57a (1 12 mg, 0.22 mmol) in THF (5 ml) at −78°C. under N₂, lithium bis(trimethylsilyl)amide (1.1 ml, 1.12 mmol, 1.0 Min THF) was added. The mixture was stirred at −78° C. for 1 h and CH₃1(70 μl, 1.12 mmol) was added. The mixture was stirred at −78° C. for 1 hbefore quenched with saturated NH₄Cl solution. Water and EtOAc wereadded to the mixture. Layers were separated and the aqueous layer wasextracted with EtOAc (100 ml×2). The combined organic layers were dried(MgSO₄) and filtered. Solvents were removed in vacuum and purificationby column chromatography [hexane-ether, 3:1 (v/v)] gave Example 58 (92mg, 78%) as colorless oil. Electrospray MS [M+1]⁺=530.1.

Example 59

Example 59 (75%) was prepared from Example 57b in a manner similar tothat used to prepare Example 58 from Example 57a. Electrospray MS[M+1]⁺=530.1.

Examples 60a and 60b

Step 1:

To a solution of Compound 48 (0.5 g, 0.77 mmol, 1 equiv) in CH₂Cl₂ (30ml) was added di tert-butyl dicarbonate (0.37 g, 1.69 mmol, 2.2 equiv)followed by DMAP (0.035 g, 0.286 mmol, 0.37 equiv) and the reactionmixture was stirred at 23° C. for 18 h. The reaction mixture was thenfiltered through a short pad of silica using (1:1 hexane:EtOAc) andconcentrated in vacuo to afford diBoc-hydantoin (0.59 g, 90%). ThediBoc-hydantoin (0.59 g, 0.7 mmol, 1 equiv) was dissolved in THF (30 ml)and 1 M aq. LiOH solution (5.56 ml, 5.56 mmol, 8 equiv) was added. Thereaction mixture was stirred at 23° C. for 18 h. Saturated aq. NaHCO₃was added to the reaction mixture and extracted with EtOAc (100 ml×3).The combined organic layers were dried (Na₂SO₄), filtered andconcentrated to give crude Compound 53 (0.52 g) which was used in thenext reaction without further purification.

Step 2:

To a mixture of crude Compound 53 (0.52 g) in pyridine (3 ml) and THF (2ml) at 0° C. was added acetyl chloride (0.072 ml, 1 mmol, 1.2 equiv) andthe reaction mixture was warmed to 23° C. and stirred for 18 h. Thereaction mixture was then concentrated and purified by columnchromatography over Biotage (5:95, MeOH:EtOAc) to afford a yellow oil ofN-acelyated product (0.31 g, 0.456 mmol, 1 equiv.) which was dissolvedin THF (10 ml). A 2M solution of CH₃NH₂ in THF (2.3 ml, 4.6 mmol, 10equiv) was added and the reaction mixture was stirred at 23° C. for 18h. The mixture was diluted with EtOAc (100 ml) and washed with saturatedaq. NaHCO₃ (100 ml). The organic layer was were dried (Na₂SO₄), filteredand concentrated to give crude NCbz-amide which was hydrogenated toafford the mixture of two isomers Example 60a and 60b using a proceduresimilar to the preparation of Example 43a and Example 43b from Compound48. The mixture of two products was separated on HPLC “ChiralPak ADcolumn” using (1:9, IPA:hexane) to afford the more polar isomer pureExample 60a, Electrospray MS [M+1]⁺=546.1 and less polar isomer pureExample 60b, Electrospray MS [M+1]⁺=546.1.

Example 61

Example 61 was prepared from Example 43a using the procedure similar tothe preparation of Examples 60a and 60b from Compound 48, but using asolution of ammonia (0.5M in 1,4-dioxane) in place of CH₃NH₂ solution(2M in THF).

Electrospray MS [M+1]⁺=532.1.

Example 62

Step, 1:

Compound 54 was prepared from Example 43a using the procedure similar tothe preparation of Compound 53 from Compound 48. Compound 54 was used inthe next reaction without further purification.

Step 2:

To a mixture of Compound 54 (0.5 g, 1.02 mmol, 1 equiv) in THF (30 ml)was added sat. aq. NaHCO₃ followed by di tert-butyl dicarbonate (0.58 g,2.65 mmol, 2.6 equiv). The reaction mixture was stirred at 23° C. for 18h. The mixture was cooled to 0° C. and 10% aq. citric acid (20 ml) wasadded and the resulting mixture was extracted with EtOAc (100 ml×3). Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedto give crude Compound 55 (0.93 g) which was used in the next reactionwithout further purification.

Step 3:

To a solution of Compound 55 (0.93 g, 1.57 mmol, 1 equiv) in CH₂Cl₂ (15ml) was added DIEA(0.83 ml, 4.72 mmol, 3 equiv) followed by PyBOP (1.23g, 2.4 mmol, 1.3 equiv). After 15 min, 0.5M solution of ammonia in1,4-dioxane (31.5 ml, 15.75 mmol, 10 equiv) was added to the reactionmixture and stirred at for 23° C. for 18 h. The reaction mixture wasquenched with water (100 ml) and extracted with EtOAc (100 ml×3). Thecombined organic layers were dried (Na₂SO₄), filtered and concentrated.The crude product was purified by column chromatography over Biotage(1:10:89, Et₃N:MeOH:EtOAc) to afford NBoc-amide which was dissolved inCH₂Cl₂ (10 ml) and cooled to 0° C. TFA (6 ml) was added and the reactionmixture was warmed to 23° C. and stirred for 2 h. The reaction wasquenched carefully with sat. aq. NaHCO₃ (100 ml) and diluted with CH₂Cl₂(100 ml). The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by column chromatographyover Biotage (10:90, MeOH:EtOAc) to afford the desired product Example62 (0.18 g, 35% over three steps), Electrospray MS [M+1]⁺=490.1.

Example 63

Example 63 was prepared from Example 62 using the procedure similar tothe preparation of Example 14 from Example 13 and using cyclopropyl acidchloride in place of propionyl chloride and also using DIEA (1.3 equiv).

Electrospray MS [M+1]⁺=558.1.

Example 64

Example 64 was prepared from Example 62 using the procedure similar tothe preparation of Example 14 from Example 13 and using t-butyl chloridein place of propionyl chloride.

Electrospray MS [M+1]⁺=574.1.

Example 65

Step 1:

Compound 56 was prepared from Example 62 using the procedure similar tothe preparation of Example 14 from Example 13 but using acetoxyacetylchloride in place of propionyl chloride. The crude Compound 56 was usedin the next reaction without further purification.

Step 2:

The crude Compound 56 was dissolved in MeOH (5 ml), KHCO₃ (3 equiv) wasadded and the reaction mixture was stirred at 23° C. for 18 h. Thereaction mixture was concentrated and purified by column chromatographyover Biotage (10:90, MeOH:EtOAc) to afford the desired product Example65, Electrospray MS [M+1]⁺=548.1.

Example 66

Example 66 was prepared from Example 62 using the procedure similar tothe preparation of Example 14 from Example 13 and using CH₃SO₂Cl inplace of propionyl chloride.

Electrospray MS [M+1]⁺=568.1 for the Example 66.

Example 67

Example 67 was prepared from Example 62 using the procedure similar tothe preparation of Example 14 from Example 13 but usingcyclopropylsulfonyl chloride in place of propionyl chloride.Electrospray MS [M+1]⁺=594.1.

Example 68

Example 68 was prepared from Example 62 using the procedure similar tothe preparation of Example 14 from Example 13 but usingtrifluoromethanesulfonic anhydride in place of propionyl chloride.

Electrospray MS [M+1]⁺=622.1 for the Example 68.

Example 69

Example 69 was prepared from Example 62 using the procedure similar tothe preparation of Example 14 from Example 13 and using nicotinoylchloride in place of propionyl chloride.

Electrospray MS [M+1]⁺=595.1 for the Example 69.

Examples 70a and 70b

Step 1:

To a mixture of Compound 53 (4 g, 5.52 mmol, 1 equiv), toluene (46 ml)and MeOH (18 ml) at 0° C. was added TMSCH₂N₂ (2M solution in hexane,13.8 ml, 27.6 mmol, 5 equiv) and the resulting solution was stirred at0° C. for 30 min. The reaction mixture was then concentrated andpurified by column chromatography over Biotage (2:1, hexane:EtOAc) togive Compound 57 (1.8 g, 44%).

Step 2:

To a mixture of Compound 57 (1 g, 1.35 mmol, 1 equiv) in dry THF (18 ml)at 0° C. was added CH₃MgBr (1 M solution in n-butylether, 3.24 ml, 3.24mmol, 2.4 equiv.) and the resulting solution was stirred at 0° C. for 30min. The reaction mixture was then warmed to 23° C. and stirred for 18h. The reaction was quenched with saturated aq. NaHCO₃ (100 ml) andextracted with EtOAc (200 ml). The organic layer was separated, dried(Na₂SO₄), filtered and concentrated. The mixture was purified by columnchromatography over Biotage (2:1, hexane:EtOAc) to give more polarCompound 58 (0.52 g, 56%) and less polar Compound 59 (0.31 g, 34%).

Step 3:

Compound 59 was deprotected with TFA using the procedure described inthe preparation of Example 62. The resulting NCbz-aminoalcohol compoundwas hydrogenated to afford the mixture of two isomers Example 70a and70b using a procedure similar to the preparation of Examples 43a and 43bfrom Compound 48. The mixture of two products was separated on HPLC“ChiralCel OD column” using (1:9, IPA:hexane) to afford-less polarisomer Example 70a, Electrospray MS [M+1]⁺ 505.1, and more polar isomerExample 70b, Electrospray MS [M+1]⁺ 505.1.

Example 71

Compound 58 was hydrogenated to a mixture of desired products Example71a and 71b using a procedure similar to the preparation of Examples 43aand 43b from Compound 48. The mixture of two products was purified bycolumn chromatography over Biotage (1:1, hexane:EtOAc) to afford pureless polar isomer Example 71a, Electrospray MS [M+1]⁺ 531.1 and puremore polar isomer Example 71b, Electrospray MS [M+1]⁺ 531.1.

Examples 72a and 72b

Step 1:

To a solution of crude Compound 53 (19 g) in CH₂Cl₂ (300 ml) at RT, DIEA(15 ml, 0.087 mol)was added, followed by triphosgene (4.34 g, 0.015mol). The mixture was stirred at RT for 18 h and was filtered through apad of silica. Solvents were removed in vacuum to give crude Compound 60as yellow oil which was used in the next reaction without furtherpurifications.

Step 2:

To the crude Compound 60 in THF (200 ml) at 0° C., LiBH₄ (1.26 g, 0.058mol) was added in small portions. The mixture was stirred at RT for 18 hbefore quenching with saturated NH₄Cl solution. Water and EtOAc wereadded to the mixture. Layers were separated and the aqueous layer wasextracted with EtOAc (100×2). The combined organic layers were dried(MgSO₄) and filtered. Solvents were removed in vacuum and purificationby column chromatography [hexane-EtOAc, 4:1 (v/v)] gave Compound 61(12.9 g, 62% overall) as white foam.

Step 3:

Oxalyl chloride (4.2 ml, 0.048 mol) was added to a solution of DMSO (6.8ml, 0.096) in CH₂Cl₂ (300 ml) at −78° C. under N₂. The mixture wasstirred at −78° C. for 15 min before a solution of Compound 61 (8.5 g,0.012 mol) in CH₂Cl₂ (100 ml) was added. The mixture was stirred at −78°C. for a further 1 h and Et₃N (23.5 ml) was added. The cooling bath wasremoved and the mixture was warmed to RT before it was quenched withsaturated NaHCO₃ solution. Layers were separated and the aqueous wasextracted with CH₂Cl₂ (150 ml×2). The combined organic layers were dried(MgSO₄) and filtered. Removal of solvents in vacuum gave an aldehyde asyellow oil. To a mixture of NaH (1.44 g, 0.036 mol) in THF at 0° C.,methyl diethylphosphonoacetate (6.6 ml, 0.036 mol) was added. Themixture was stirred at 0° C. for 15 min and a solution of aldehyde inTHF (100 ml) was added. The cooling bath was removed and the mixture wasstirred at RT for 1 h. The reaction was quenched with saturated NH₄Clsolution. Water and EtOAc were added to the mixture. Layers wereseparated and the aqueous layer was extracted with EtOAc (200 ml×2). Thecombined organic layers were dried (MgSO₄) and filtered. Solvents wereremoved in vacuum and purification by column chromatography[hexane-EtOAc, 4:1 (v/v)] gave an ester as white foam. The ester wasdissolved in EtOH (100 ml) and a catalytic amount of palladium (1.28 g,10% on carbon) was added. The mixture was shaken under H₂ (50 psi) for 2days. Catalytic amount of Pd(OH)₂ (20% on carbon) was then added to themixture and the mixture was again shaken under H₂ (50 psi) for 5 h. Themixture was filtered through a pad of Celite and solvents were removedin vacuum to give a white foam. The foam was then dissolved in CH₂Cl₂(200 ml) and TFA (8.9 ml, 0.12 mol) was added. The mixture was stirredat RT for 18 h and was cooled at 0° C. before it was neutralized withsaturated NaHCO₃ solution. Water and EtOAc were added to the mixture.Layers were separated and the aqueous layer was extracted with EtOAc(200 ml×2). The combined organic layers were dried (MgSO₄) and filtered.Solvents were removed in vacuum to give a yellow oil. The oil wasdissolved in CH₃0H (50 ml) and a catalytic amount of K₂CO₃ (166 mg,0.0012 mol) was added. The mixture was heated at 60° C. for 2 h. Afterbeing cooled to RT, the mixture was filtered through a pad of silica andsolvents were removed in vacuum. Purification by column chromatography(EtOAc) gave the mixture of two isomers Example 72a and 72b (2.3 g, 38%overall) as white foam. Separation by HPLC using Chiralcel OD[hexane-isopropanol, 95:5 (v/v)] gave the less polar major isomerExample 72a as white foam. Electrospray MS [M+1]⁺=501.1. Continuouselution with the same solvent system gave the more polar minor isomerExample 72b as colorless oil.

Electrospray MS [M+1]⁺=501.1.

Examples 73a and 73b

To a solution of Compound 61 (3 g, 4.22 mmol, 1 equiv) in DMF (60 ml) at0° C. was added NaH (60% in mineral oil, 0.122 g, 5.07 mmol, 1.2 equiv)and the mixture was allowed to warm to 23° C. and stirred for 45 min.The reaction was quenched with water (100 ml) and extracted with EtOAc(100 ml×3). The combined organic layers were dried (MgSO₄), filtered andconcentrated. The crude product purified by column chromatography overBiotage (2:1, hexane:EtOAc).to afford the desired product which washydrogenated to afford the mixture of two isomers Example 73a and 73busing a procedure similar to the preparation of Examples 43a and 43bfrom Compound 48. The mixture of two products was separated on HPLC“ChiralPak AD column” using (5:95, IPA:hexane) to afford pure less polarisomer Example 73a and more polar isomer Example 73b.

Electrospray MS [M+1]⁺=503.1 for Example 73a.

Electrospray MS [M+1]⁺=503.1 for Example 73b.

Example 74

Compound 61 (1.68 g, 2.36 mmol, 1 equiv) was dissolved in CH₂Cl₂ (50ml), TFA (5.46 ml, 70.9 mmol, 30 equiv) was added and the reactionmixture was stirred at 23° C. for 2.5 h. The reaction was quenchedcarefully with sat. aq. NaHCO₃ (150 ml) and diluted with CH₂Cl₂ (100ml). The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated to give crude amino-alcohol product (1.4 g, 97%). Theproduct (0.32 g, 0.524 mmol, 1 equiv) was dissolved in dry THF (10 ml)and NaH (60% in mineral oil, 0.025 g, 0.63 mmol, 1.2 equiv.) was added.The reaction mixture was stirred at 23° C. for 5 min and then ethylchloroacetate (0.062 ml, 0.576 mmol, 1.1 equiv) was added and thereaction mixture was stirred for 2.5 h. The reaction was quenchedcarefully with sat. aq. NaHCO₃ (100 ml) and diluted with EtOAc (200 ml).The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by column chromatographyover Biotage (2:3, hexane:EtOAc) to give the product (0.1 g, 32%) whichwas hydrogenated to afford the mixture of two isomers Example 74a and74b using a procedure similar to the preparation of Examples 43a and 43bfrom Compound 48. The mixture of two products was separated on HPLC“ChiralCel OD column” using (1:9, IPA:hexane) to afford pure Example74a, Electrospray MS [M+1]⁺ 517.1, and pure Example 74b, Electrospray MS[M+1]⁺ 517.1.

Example 75

Step 1:

Compound 57 was converted to Compound 62 (72% yield over two steps)using the PyBOP coupling followed by TFA deprotection procedures asdescribed in the preparation of Example 62 from Compound 55 but usingCompound 57 (1 equiv.) in place of ammonia and NH-Boc-glycine (2 equiv.)in place of Compound 55.

Step 2:

Compound 62 (0.5 g, 0.72 mmol, 1 equiv) was dissolved in MeOH (10 ml)and Et₃N (1 ml, 7.2 mmol, 10 equiv) was added. The resulting mixture washeated at 23° C. for 18 h. The reaction mixture was then concentratedand purified by column chromatography over Biotage (EtOAc) to giveNCbz-diketopiperazine (0.33 g) which was hydrogenated to afford themixture of two isomers Example 75a and 75b using a procedure similar tothe preparation of Examples 43a and 43b from Compound 48. The mixture oftwo products was separated on HPLC “ChiralPak AD column” using (5:95,IPA:hexane) to afford pure less polar isomer Example 75a (0.03 g, 8%over two steps), Electrospray MS [M+1]⁺ 530.1, and more polar isomerExample 75b, (0.04 g, 11% over two steps), Electrospray MS [M+1]⁺ 530.1.

Examples 76a and 76b

Compound 51 (3.66 g, 5.76 mmol, 1 equiv.) was hydrogenated using aprocedure similar to the preparation of Examples 43a and 43b fromCompound 48 and the hydrogenated product (2.85 g) was treated withCH₃NH₂ (2M solution in CH₃OH, 200 ml) and stirred at 23° C. for 18 h.The reaction mixture was then concentrated and purified by columnchromatography over Biotage (1:9, MeOH:EtOAc) to give the mixture of twoisomers Example 76a and 76b. The mixture of two isomers was separated onHPLC “ChiralPak AD column” using (5:95, IPA:hexane) to afford less polarisomer Example 76b, Electrospray MS [M+1]⁺ 503.1, and more polar isomerExample 76a, Electrospray MS [M+1]⁺ 503.1.

Example 77

Example 62 (0.07 g, 0.133 mmol, 1 equiv) was dissolved in CH₂Cl₂ (3 ml)and DIEA (0.03 ml, 0.147 mmol, 1.1 equiv) was added followed by4-methoxyphenyl (pmb)-isocyanate (0.021 ml, 0.147 mmol, 1.1 equiv) andthe reaction mixture was stirred at 23° C. for 18 h. The reactionmixture was then concentrated and treated with CH₃CN (3 ml) and water (1ml) and the mixture was cooled to 0° C. Ammonium cerium nitrate (0.24 g,0.44 mmol, 4 equiv) was added and the reaction mixture was stirred at 0°C. for 45 min. The reaction was quenched with saturated aq. NaHCO₃ (100ml) and extracted with EtOAc (200 ml). The organic layer was separated,dried (Na₂SO₄), filtered and concentrated. The mixture was purified bycolumn chromatography over Biotage (15:85, MeOH:EtOAc) to give Example77 (0.03 g, 42%), Electrospray MS [M+1]⁺ 533.1.

Examples 78a and 76b

Step 1:

In a flame dry 15 ml RBF Compound 48 (0.25 g, 0.385 mmol, 1 equiv) inDMF (1 ml) was added to K₂CO₃ (0.106 g, 0.77 mmol, 2 equiv) followed by2-bromoethanol (0.033 ml, 0.46 mmol, 1.2 equiv) and the mixture wasstirred for 2 h at RT, then heated to 50° C. for 6 h. The reaction wasmonitored by TLC (60/40 EtOAc/Hexane). The reaction mixture was cooledto 0° C., quenched with H₂O, diluted with EtOAc and washed with brine.The organic layer was combined and dried over Na₂SO₄, filtered andconcentrated. The reaction mixture was purified using Biotage using 2:3EtOAc/Hexane to 3:2 EtOAc/Hexane to elute Compound 63 as a mixture oftwo isomers (0.258 g, 97%), Electrospray MS [M+1]⁺ 694.1.

Step 2:

To a solution of Compound 63 (0.25 g, 0.36 mmol, 1 equiv) in anhydrousMeOH was added (5.5 ml) 20% Pd(OH)₂/C (0.08 g). The reaction mixture waspurged with N₂ followed by H₂ and stirred for 18 h under H₂. Thereaction was monitored by TLC (60/40 EtOAc/Hexane). The catalyst wasfiltered through a plug of celite and the solution was concentrated togive crude product. The material was subjected to flash chromatographyusing a Biotage (80:20 EtOAc/Hexane). The isomers were separated to giveExample 78a and Example 78b (0.13 g, 63%).

Electrospray MS [M+1]⁺ 560.1 for Example 78a (less polar isomer);

Electrospray MS [M+1]⁺ 560.1 for Example 78b (more polar isomer).

Examples 79a and 79b

Step 1:

N-(Boc)-methanesulfonamide (0.041 g, 0.43 mmol, 1.5 equiv) was dissolvedin dry THF (1 ml) and triphenyl phosphine (0.228 g, 0.43 mmol, 3 equiv)was added. The resulting solution was stirred under N₂ and a solution ofCompound 63 (0.2 g, 0.29 mmol, 1 equiv) in THF followed by diethylazodicarboxylate (DEAD) (0.12 ml, 0.26 mmol, 2.5 equiv) were added. Thereaction monitored by TLC (60/40 EtOAc/Hexane). Upon completion, thereaction mixture was concentrated to give a yellow oil which wassubjected to flash chromatography using a Biotage (1:1 EtOAc/Hexane) toelute the product, Compound 64, as a mixture of two isomers (0.24 g,95%), Electrospray MS [M+1]⁺ 871.1.

Step: 2

To a solution of Compound 64 (0.25 g, 0.29 mmol, 1 equiv) in dry CH₂Cl₂(10 ml) at 0° C. was added 4M HCl in dioxane (0.755 ml, 2.9 mmol, 10equiv). The reaction was warmed to RT and monitored by TLC (60/40EtOAc/Hexane). Upon completion the reaction was quenched with water,diluted with CH₂Cl₂, washed with saturated NaHCO₃, and dried over Na₂SO₄to give crude Compound 65 as a mixture of two isomers (0.2 g, 89%). Thecrude material was carried forward without any purification.

Electrospray MS [M+1]⁺ 771.1 for Compound 65.

Step: 3

To a solution of Compound 65 (0.2 g, 0.26 mmol, 1 equiv) in MeOH (5 ml)was added 10% Pd/C followed by ammonium formate (0.082 g, 1.3 mmol, 5equiv). The reaction was refluxed under N₂ for 3 h, then cooled to RT,filtered through celite, and concentrated. The residue was dissolved inEtOAc, washed with NaHCO₃ and dried over Na₂SO₄. The crude material wassubjected to prep plate chromatography. Both of the isomers wereisolated to give pure Example 79a and Example 79b (0.06 g, 36% total forboth isomers).

Electrospray MS [M+1]⁺ 637.1 for Example 79a (less polar isomer);

Electrospray MS [M+1]⁺ 637.1 for Example 79b (more polar isomer).

Example 80

To a solution of Example 62 (0.079 g, 0.127 mmol, 1 equiv) in dry CH₂Cl₂(1 ml) was added Et₃N (0.108 ml, 0.76 mmol, 6 equiv). The reactionmixture was cooled to 0° C. and stirred for 15 min. SO₂Cl₂ (0.011 ml,0.133 mmol, 1.05 equiv) was added very slowly to the reaction over 5min. The reaction stirred for 10 h and was monitored by TLC (9:1EtOAc/CH₃OH). The reaction mixture was diluted with EtOAc, washed withNaHCO₃, and dried over Na₂SO₄. The crude product was subjected to prepplate chromatography to isolate Example 80 (0.015 g, 20%), ElectrosprayMS [M+1]⁺ 552.1.

Example 81

Step 1:

Compounds 66a and 66b were prepared from Compound 48 using a proceduresimilar to the preparation of Example 62 from Example 43a.

Step 2:

To a solution of Compound 66a (0.34 g, 0.545 mmol, 1 equiv) in drytoluene (14 ml) was added HOAc (0.17 ml) followed by triethylorthoformate (0.363 ml, 2.18 mmol, 4 equiv). The solution was refluxedfor 12 h and monitored by TLC (9:1 EtOAc/CH₃OH). The reaction was cooledto 0° C., quenched with H₂O, diluted with EtOAc, washed with NaHCO₃, anddried over Na₂SO₄. The crude was subjected to flash chromatography usinga Biotage (60:40 EtOAc/Hexane) to elute Compound 67a (0.272 g, 79%),Electrospray MS [M+1]⁺ 634.1.

Step3:

Example 81 was prepared from Compound 67a using a similar procedure asfor Examples 79a and 79b from Compound 65.

Electrospray MS [M+1]⁺ 500.1 for Example 81.

Example 82

Step 1:

To a solution of a mixture of the two isomers of Compound 67 (0.27 g,0.426 mmol, 1 equiv) in dry CH₃OH (3 ml) was added NaBH₄ (0.048 g, 1.28mmol, 3 equiv). The reaction mixture bubbled upon the addition of thereagent, and was stirred for 5 h under N₂. The reaction was monitored byTLC (60/40 EtOAc/Hexane), and upon completion was quenched with HOAc,concentrated, diluted with EtOAc, washed with NaHCO₃ and dried overNa₂SO₄. The crude product was a mixture of two isomers, Compound 68,(0.25 g, 92%) and was carried forward without any purification.

Electrospray MS [M+1]⁺ 636.1 for the Compound 68.

Step2:

Example 82a (less polar isomer) and Example 82b (more polar isomer)(0.12 g, 61%) were prepared from Compound 68 using a similar procedureas for preparing Examples 79a and 79b from Compound 65.

Electrospray MS [M+1]⁺ 502.1 for Example 82a,

Electrospray MS [M+1]⁺ 502.1 for Example 82b.

Example 83

Step 1:

To a solution of Compound 66a (0.1 g, 0.16 mmol, 1 equiv) in a 25 ml RBFin MeOH (0.5 ml) was added acetone (0.352 ml, 0.48 mmol, 3 equiv) andp-TsOH (0.06 g, 0.32 mmol, 2 equiv). The reaction mixture was refluxedfor 12 h and was monitored by mass spectrum analysis. Reaction uponcompletion was concentrated, diluted with EtOAc, washed with NaHCO₃, anddried over Na₂SO₄ to give Compound 69 (0.1 g, 94%). The crude productwas carried forward without any purification.

Step 2:

Example 83 (0.026 g, 33%) was prepared from Compound 69 using a similarprocedure as for preparing Examples 79a and 79b from Compound 65.

Electrospray MS [M+1]⁺ 530.1 for Example 83.

Examples 84a and Example 84b

Examples 84a and Example 84b were prepared using a similar procedure asfor Examples 78a and 78b, but using 2-bromoethyl methyl ether instead of2-bromoethanol.

Electrospray MS [M+1]⁺ 574.1 for Example 84a,

Electrospray MS [M+1]⁺ 574.1 for Example 84b.

Example 85

Example 85 (46 mg, 88%) was prepared from Example 43b using a similarprocedure as for Compound 63, but using allyl bromide instead of2-bromoethanol.

Electrospray MS [M+1]⁺ 556.1.

Examples 86a and Example 86b

Step 1:

Compound 70 (1.14, 99%) was prepared. from Compound 48 using a similarprocedure as for Compound 63 but using para-methoxybenzyl chlorideinstead of 2-bromoethanol. Electrospray MS [M+1]⁺ 770.2.

Step 2:

To a solution of Compound 70 (0.19 g, 0.25 mmol, 1 equiv) in 1.0 ml ofanhydrous DMF at 0° C. was added NaH (60% dispersion in mineral oil,0.012 g, 0.30 mmol, 1.2 equiv). After 5 min, the ice bath was removedand the reaction mixture was allowed to stir for 30 min before theaddition of bromomethyl cyclopropane (0.029 ml, 0.30 mmol, 1.2 equiv).After 20 h, the reaction mixture was quenched with saturated NH₄Clsolution and diluted with EtOAc. The layers were separated and theorganic layer was washed once with brine, dried over Na₂SO₄, filteredand concentrated to give Compound 71 (0.11 g, 99%) Electrospray MS[M+1]⁺ 824.2.

Step 3:

Compound 72 (0.24 g, 90%) was prepared from Compound 71 using a similarprocedure as for Examples 78a and 78b from Compounds 63. Electrospray MS[M+1]⁺ 690.1.

Step 4:

To a solution of Compound 72 (0.24 g, 0.34 mmol, 1 equiv) in 5.0 ml ofCH₃CN and 1.7 ml of water at 0° C. was added ammonium cerium nitrate(0.79 g, 1.4 mmol, 4 equiv). After 5 min the ice bath was removed andthe reaction mixture was allowed to stir at RT for 17 h. The reactionmixture was quenched with water and diluted with EtOAc. The layers wereseparated and the organic layer was washed with water (100 ml×2), driedover Na₂SO₄, filtered and concentrated to give a yellow oil.Purification by chromatography on a Biotage eluting with the solventgradient 20% EtOAc/hexane to 30% EtOAc/hexane to 50% EtOAc/hexane gave adiastereomeric mixture of Examples 86a and 86b (15 mg, 8%), isomericallypureless polar Example 86a (14 mg, 7%) Electrospray MS [M+1]⁺ 570.1, andisomerically pure more polar Example 86b (16 mg, 9%) Electrospray MS[M+1]⁺ 570.1.

Example 87

Step 1:

Compound 73 (0.20, 64%) was prepared from Compound 48 using a similarprocedure as for Compound 63. Electrospray MS [M+1]⁺ 814.19.

Step 2:

Compound 74 (0.16 g, 96%) was prepared from Compound 73 using a similarprocedure as for Examples 78a and 78b from Compound 63. Electrospray MS[M+1]⁺ 680.1.

Step3:

Examples 87a and 87b were prepared from Compound 74 using a similarprocedure as for Example 86a and 86b from Compound 72, but purificationusing a Gilson with water/CH₃CN was used instead of chromatography on aBiotage to isolate a diastereomeric mixture of Examples 87a and 87b (92mg, 71%). HPLC separation on 50 mg of the mixture on a ChiralCel ODcolumn using a (90/10) hexane/IPA as the eluent gave a diastereomericmixture of Example 87a and 87b (11 mg), isomerically pure first-elutedproduct Example 87a (10 mg) Electrospray MS [M+1]⁺ 560.1, andisomerically pure second-eluted product Example 87b (11 mg)

Electrospray MS [M+1]⁺ 570.1.

Example 88

A diastereomeric mixture of Example 88a and 88b (22% overall yield inthree steps from Compound 70) was prepared using a similar procedure asfor Example 86a and 86b, but using 2-bromoethyl methyl ether instead ofbromomethyl cyclopropane. HPLC separation on 50 mg of the diastereomericmixture on a ChiralCel OD column using a (90/10) hexane/IPA as theeluent gave isomerically pure first-eluted product Example 88a (16 mg)Electrospray MS [M+1]⁺ 574.3, and isomerically pure second-elutedproduct Example 88b (29 mg) Electrospray MS [M+1]⁺ 574.3.

Example 89

To a solution of Example 43b (0.68 g, 1.32 mmol, 1 equiv) in DMF (7 ml)at 0° C. was added NaH (60% in mineral oil, 0.105 g, 2.64 mmol, 2 equiv)and the mixture was stirred at 0° C. for 15 min. Tetravbenzylpyrophosphate (1.42 g, 2.64 mmol, 2 equiv) was added and the reactionmixture stirred at 0° C. for 15 min, then warmed to 23° C. and stirredfor 1 h. The reaction was quenched with saturated aq. NaHCO₃ (100 ml)and extracted with EtOAc (100 ml×3). The combined organic layers weredried (Na₂SO₄), filtered and concentrated. The crude product purified bycolumn chromatography over Biotage (2:1, hexane:EtOAc) to afford theN-phosphorated hydantoin product (0.24 g) which was dissolved in MeOH(10 ml); N-Me-D-glucamine (0.119, 0.619 mmol, 2 equiv) was added,followed by 10% Pd—C (0.021 g). The resulting mixture was shaken in aparr shaker under H₂ atmosphere at 40 psi for 18 h. The reaction mixturewas filtered through a pad of celite and the celite was washed withMeOH. The resulting solution was concentrated in vacuo. The residue wasdissolved in EtOAc (100 ml) and extracted with water (100 ml) and theaqueous layer was lyophilized to give the desired product Example 89 asN-Me-D-glucamine salt (0.22 g, 21% over two steps).

Example 90

Step 1:

Compound 75 was prepared from Compound 48 using a procedure similar tothe preparation of Compound 66 from Compound 48.

Step 2:

To a solution of the diastereomeric Compound 75 (0.10 g, 0.16 mmol, 1equiv) in 2.0 ml of anhydrous CH₂Cl₂ at 0° C. was added Et₃N (0.033 ml,0.24 mmol, 1.5 equiv) and 4-chlorobutyrylchloride (0.017 ml, 0.17 mmol,1.1 equiv). After 6 h, the reaction mixture was quenched with saturatedNH₄Cl solution and diluted with EtOAc. The layers were separated and theorganic layer was washed once with brine, dried over Na₂SO₄, filteredand concentrated to give Compound 76 as a diastereomeric mixture (0.12g, 100%) Electrospray MS [M+1]⁺ 742.2.

Step3:

To a solution of Compound 76 (0.12 g, 0.16 mmol, 1 equiv).in 1.0 ml ofanhydrous THF at RT was added NaH (60% dispersion in mineral oil, 0.010g, 0.24 mmol, 1.5 equiv). After 3 h, the reaction mixture was quenchedwith saturated NH₄Cl solution and diluted with EtOAc. The layers wereseparated and the organic layer was washed once with brine, dried overNa₂SO₄, filtered and concentrated to give Compound 77 (0.10 g, 88%)Electrospray MS [M+1]⁺ 706.2.

Step 4:

Examples 90a and 90b were prepared from Compound 77 using a similarprocedure as for preparing Example 83 from Compound 69, but purificationused chromatography on a Biotage instead of a Prep plate. Adiastereomeric mixture of Examples 90a and 90b (26 mg, 32%)was obtained:less polar product Example 90a (20 mg, 25%) Electrospray MS [M+1]⁺572.1, more polar product Example 90b (14 mg, 17%) Electrospray MS[M+1]⁺ 572.1.

Example 91

Step 1:

To a solution of Compound 47 (1 g, 1.73 mmol, 1 equiv) andtosylmethyl-isocyanide (374 mg, 1.9 mmol, 1.1 equiv) in anhydrousethylene glycol dimethylether (11 ml) at −30° C., was added anhydrousMeOH (0.15 ml) followed by addition of potassium tert-butoxide (426 mg,3.8 mmol, 2.2 equiv). After stirring at −30° C. to 10° C. for 7 h, thereaction mixture was passed through celite. The celite pad wasthoroughly washed with Et₂O. The filtrate was concentrated and theresidue was purified on silica gel column to afford the titled Compound78 (470 mg, 46%).

Step 2:

A solution of Compound 78 (125.7 mg, 0.21 mmol, 1 equiv) and NH₄Cl (68.3mg, 1/28 mmol, 6 equiv) and NaN₃ (69.2 mg, 1.06 mmol, 5 equiv) inanhydrous DMF (1.2 ml) under N₂ was heated at 115° C. overnight. Themixture was concentrated, then acidified with HCl (6N, 10 ml) andextracted with EtOAc (15 ml×3). The combined organic solvent was driedover Na₂SO₄, filtered and evaporated in vacuum. The residue was purifiedon a silica gel column to afford Compound 79 (67 mg, 50%).

Step 3:

A solution of Compound 79 (65 mg, 0.103 mmol, 1 equiv) in EtOH (1.5 ml)was treated with 10% Pd—C (107 mg, 0.1 mmol, 1. equiv) and1,4-cyclohexadiene (0.5 ml, 5.29 mmol, 50 equiv). The mixture was heatedat 85° C. for 10 min, then passed through celite. The celite pad waswashed with MeOH. The filtrate was concentrated in vacuum and theresidue was purified by silica gel column to afford Example 91 (11 mg,21%) Electrospray.MS [M+1]⁺ 500.1.

Example 92

Step 1:

Compound 80 (72% yield) was prepared by similar procedure as forCompound 23 using Compound 47 in place of Compound 3.

Step 2:

To a solution of triethyl 2-chloro-2-phophonoacetate (73 μl, 0.34 mmol,1.05 equiv) in anhydrous THF (1.5 ml) at −78° C., was added dropwise ofLiHMDS (0.35 ml, 0.35 mmol, 1.1 equiv, 1N solution in THF). The solutionwas stirred for 20 min before a solution of Compound 80 (192 mg, 0.32mmol, 1 equiv) in dry THF (1 ml) was cannulated in. It was stirred at−78° C. for 2 h then quenched with saturated NH₄Cl aqueous solution, andextracted with Et₂O. The organic layer was dried over MgSO₄, filteredand concentrated to give the crude product which was purified by silicagel column to give Compound 81 (127 mg, 57%).

Step 3:

To a solution of Compound 81 (127 mg, 0.18 mmol, 1.0 equiv) in EtOH (1ml) was added H₂NNH₂ (35 μl, 1.1 mmol, 6 equiv). It was stirred for 3 hand then concentrated in vacuum. The crude product was retaken up intoEtOH (3 ml) and treated with 10% Pd/C (40 mg, 0.036 mmol, 0.2 equiv) andhydrogenated overnight. The catalyst was filtered off and washed withMeOH. The filtrate was concentrated to give the crude residue which waspurified on silica gel column to afford less polar isomer Example 92a(14.2 mg, 15%), Electrospray MS [M+1]⁺ 514.1; and more polar isomerExample 92b (28.1 mg, 30%), Electrospray MS [M+1]⁺ 514.1

Example 93

Step 1:

Compound 80 (0.74 g, 1.25 mmol, 1 equiv), was dissolved in t-BuOH (20ml) and 2-methyl-2-butadiene (7 ml). To this solution was added a freshsolution of NaClO₂ (1.13 g, 12.5 mmol, 10 equiv.) in 20% (v/w) aq.NaH₂PO₄ solution. The reaction mixture was stirred at RT for 2 h. It wasthen diluted with EtOAc (200 ml) and the organic layer was separated,dried (Na₂SO₄), filtered and concentrated to give the crude Compound 82which was used in the next reaction without further purification.

Step 2:

To a solution of the diastereomeric Compound 82 (0.33 g, 0.54 mmol, 1equiv) in 2 ml of anhydrous CH₂Cl₂ at RT was sequentially added DIEA(0.11 ml, 0.65 mmol, 1.2 equiv), DEC (0.21 g, 1.1 mmol, 2 equiv),3-hydroxy-1,2,3-benzotriazin4(3H)-one (0.18 g, 1.1 mmol, 2 equiv), andsemicarbazide hydrochloride (0.072 g, 0.65 mmol, 1.2 equiv). After 3 h,the starting carboxylic acid was present by TLC [Hexane-EtOAc 1:1 (v/v)]and an additional amount of DIEA (0.11 mL, 0.65 mmol, 1.2 equiv) wasadded. After 2 days, the reaction mixture was quenched with saturatedNaHCO₃ solution and diluted with EtOAc. The layers were separated andthe organic layer was washed once with water and brine, dried overNa₂SO₄, filtered and concentrated to give an orange oil. Purification bychromatography on a Biotage eluting with the solvent gradient 50%EtOAc/hexane to 80% EtOAc/hexane to EtOAc to 5% MeOH/EtOAc gave Compound83 as a.diastereomeric mixture (0.19 g, 54%) Electrospray MS [M+1]⁺667.07.

Step 3:

A solution of Compound 83 (0.17 g, 0.26 mmol, 1 equiv) in 8 ml of 2.0MNaOH solution was heated to reflux. After 15 h, the mixture was allowedto cool to RT and was neutralized with 1.0M HCl to pH6. The aqueoussolution was diluted with EtOAc and the layers were separated. Theorganic layer was washed once with brine, dried over Na₂SO₄, filteredand concentrated to give a yellow oil (0.16 g). Purification bychromatography on a Biotage eluting with 3% MeOH/EtOAc gave Compound 84as a diastereomeric mixture (0.12 g, 71%) Electrospray MS [M+1]⁺ 649.2.

Step 4:

Less polar product Example 93a and more polar product Example 93b (32 mgand 44 mg, total 88% for both isomers) were prepared from Compound 84using a similar procedure as for preparing Examples 79a and 79b fromCompound 65, but purification used chromatography on a Biotage insteadof a Prep plate.

Electrospray MS [M+1]⁺ 515.3 for Example 93a.

Electrospray MS [M+1]⁺ 515.3 for Example 93b.

Example 94

Step 1:

To a solution of Compound 80 (550 mg, 0.98 mmol, 1 equiv) in anhydrousTHF (6 ml) at −10° C., was added dropwise CH₃MgBr (1.24 ml, 3.7 mmol, 4equiv, 3.0M solution in Et₂O). The solution was stirred at −10° C. to10° C. for 30 min. Aqueous work-up gave the crude product which waspurified on silica gel column to afford Compound 85 (236 mg, 42%).

Step 2:

To a solution of DMSO (0.11 ml, 1.55 mmol, 4 equiv) in anhydrous CH₂Cl₂(5 ml) at −78° C., was added dropwise oxalyl chloride (0.067 ml, 0.78mmol, 2 equiv). The solution was stirred for 15 min before a solution ofCompound 85 (236 mg, 0.387 mmol, 1 equiv) in dry CH₂Cl₂ (1 ml) wascannulated in. It was stirred at −78° C. for 1 h, then Et₃N (0.37 ml,2.71 mmol, 7 equiv) was added dropwise. After stirring at −78° C. for 30min, the cooling bath was removed and the reaction was warmed up to RT.It was quenched with saturated NH₄Cl aqueous solution, and extractedwith CH₂Cl₂. The organic layer was dried over MgSO₄, filtered andconcentrated to give the crude product, which was purified by silica gelcolumn to give Compound 86 (140 mg, 60%).

Step 3:

To a solution of Compound 86 (1.0 equiv) in EtOH (3mi) was added 10%Pd/C (0.4 equiv) and the mixture hydrogenated overnight in a H₂ balloonatmosphere. The catalyst was filtered off and washed with MeOH. Thefiltrate was concentrated to give the crude residue which was purifiedon silica gel column to affordless polar isomer Example 94a (24 mg,22%), Electrospray MS [M+1]⁺ 474.1; and more polar isomer Example 94b(32 mg, 29%), Electrospray MS [M+1]⁺ 474.1

Example 95

To a solution of Example 94a (16 mg, 0.033 mmol, 1 equiv) in anhydrousEtOH (1 ml) was added hydroxylamine hydrochloride salt (18 mg, 0.26mmol, 7.7 equiv), and NaOAc (5 mg, 0.061 mmol, 1.8 equiv). The reactionmixture was stirred at RT overnight, then concentrated to dryness. Theresidue was retaken up with Et₂O, and washed with saturated NaHCO₃aqueous solution. The organic layers were dried over MgSO4, filtered andconcentrated in vacuum. The crude product was purified on silica gelcolumn to afford Example 95 (12 mg, 74%), Electrospray MS [M+1]⁺ 489.1

Example 96

Example 96 (13 mg, 50%) was prepared by similar procedure as for Example95 but using Example 94b in place of Example 94a. Electrospray MS [M+1]⁺489.1.

Example 97

Step 1:

To a solution of ethyl vinylether (0.5 ml, 4.83 mmol, 12 equiv) inanhydrous THF (6 ml) at −78° C., was added dropwise tBuLi (0.73 ml, 1.24mmol, 3 equiv, 1.7N solution in pentane). The solution was stirred at−10° C. bath until the orange color faded away. It was cooled to −78° C.again, and a solution of Compound 47(240 mg, 0.41 mmol, 1 equiv) in dryTHF (1 ml) was cannulated in. It was stirred at −78° C. for 1.5 h thenwas quenched with saturated NH₄Cl aqueous solution and extracted withEt₂O. The organic layer was dried over MgSO₄, filtered and concentratedto give the crude product, which was retaken up into THF (6 ml) andtreated with 10% HCl aqueous solution (0.8 ml). It was stirred at RTovernight. Alkaline aqueous work-up gave the crude product which waspurified on silica gel column to afford Compound 87 (100 mg, 39%).

Step 2:

Compound 88a and Compound 88b were prepared using a similar procedure asfor Examples 94a and 94b using Compound 87 instead of Compound 86.Separation by chiral HPLC column afforded Compound 88a (13 mg, 18%), andCompound 88b (10 mg, 14%).

Step 3:

Example 97a (9.7 mg, 71%) was prepared using similar procedure as forExample 95 using Compound 88a in place of Example 94a. Electrospray MS[M+1]⁺ 505.1

Step 4:

Example 97b (10.7 mg, 100%) was prepared using similar procedure as forExample 95 using Compound 88b in place of Example 94a. Electrospray MS[M+1]⁺ 505.1

Example 98 and Example 99

To Example 13 (340 mg, 0.76 mmol) in 1 ml toluene was added Pd₂(dba)₃(27.8 mg, 0.03 mmol), BINAP (37.8 mg, 0.06 mmol), 2-bromopyridine (73μl, 0.76 mmol) and NaOtBu (102 mg, 1.065 mmol). The mixture wasconcentrated in vacuo and the flask filled with N₂. The process wasrepeated once. The dark-brown solution was heated at 90° C. for 16 h. Itwas cooled to 23° C. and quenched with 2 ml pH7 buffer. The solution wasextracted with EtOAc (10 ml×2). The organic layers were dried overNa₂SO₄ and concentrated. HPLC separation give Example 98, ElectrosprayMS M+1]⁺ 524.1; and Example 99, Electrospray MS [M+1]⁺ 601.1.

Example 100

Example 100 was prepared using a similar procedure to Example 98, using2-bromopyrimidine in place of 2-bromopyridine. Electrospray MS [M+1]⁺525.1.

Example 101

Example 101 was prepared using a similar procedure to Example 98, using2-chloro-3-cyanopyridine in place of 2-bromopyridine. Electrospray MS[M+1]⁺ 549.1.

Example 102

Step 1:

To Compound 85 (429 mg, 0.704 mmol) in CH₂Cl₂ (3.5 ml) at 0° C. wasadded Cl₃CONCO (100 ml, 0.844 mmol) dropwise. The solution was stirredat 0° C. for 2 h. The solvent was then removed and the residue wasdissolved in MeOH (4 ml) and H₂O (1 ml). K₂CO₃(1.0 g) was added and thesuspension was stirred for 14 h. The mixture was then diluted with 3 mlof water, concentrated to remove MeOH. The residue was extracted withEtOAc (10 ml×3). The combined organic layers were concentrated andpassed through a short silica gel column to give product Compound 88(420 mg, 91%).

Step 2:

To Compound 88 (290 mg, 0.446 mmol) in CH₂Cl₂ (3 ml) was added Phl(OAc)₂(131 mg, 0.625 mmol), Rh₂(OAc)₄ (12.9 mg, 0.022 mmol) and MgO (26.4 mg,1.0 mmol). The suspension was heated at 40° C. for 16 h then cooled to23° C. Celite (0.5 g) was added and the suspension was stirred for 5min. The mixture was filtered and washed with EtOAC. The combinedfiltrate was concentrated and purified by chromatography on silica gelto give Compound 89 (60 mg, 31%).

Step 3:

Compound 89 transferred to a Parr shaker using 5 ml EtOH. 10% Pd—C (10%,60 mg) was added and the suspension was hydrogenated at 40 psiovernight. The reaction mixture was filtered and concentrated. Theresidue was separated using HPLC on OD column eluted with 1:9 IPA/hexaneto give two isomers, less polar isomer Example 102a, Electrospray MS[M+1]⁺ 517.1 and more polar isomer Example 102b, Electrospray MS [M+1]⁺517.1.

Example 103

Step 1:

To a mixture of methyl diethylphosphonoacetate (9.5 ml, 51.77 mmol, 3equiv) in dry THF (100 ml) at 0° C. under N₂ was added NaH (60% inmineral oil, 1.24 g, 51.77 ml, 3 equiv.). After being stirred at 0° C.for 15 min, a solution of Compound 3 (10 g, 17.26 mmol, 1 equiv) in THF(250 ml) was added. The mixture was warmed to 23° C. and stirred for 1 hand then quenched with saturated aq. NaHCO₃ solution (100 ml). Themixture was extracted with EtOAc (100 ml×3). The combined organic layerswere dried (MgSO₄) and filtered. The crude product was purified bycolumn chromatography over Biotage (4:1, hexane:EtOAc then 1:1,hexane:EtOAc) to afford the Compound 90 (8.88 g, 86%), Electrospray MS[M+1]⁺ 596.1.

Step 2:

Compound 91 was prepared from Compound 90 using the procedure similar tothe preparation of Compound 44 from Compound 42. The crude Compound 91was used in the next reaction without further purification.

Step 3:

To a solution of Compound 91 (8.8 g, 14.73 mmol, 1 equiv.) in dry THF(150 ml) was added LiBH₄ (0.58 g, 26.51 mmol, 1.8 equiv.) and thereaction mixture was stirred at 0° C. for two h. The reaction mixturewas cooled to 0° C. over an ice bath and quenched with saturated NaHCO₃(50 ml). The reaction mixture was extracted with EtOAc (3×100 ml). Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedto give crude Compound 92 (8.2 g), Electrospray MS [M+1]⁺ 570.1, whichwas used in the next reaction without further purification.

Step 4:

To a solution of Compound 92 (8.2 g, 14.4 mmol, 1.0 equiv.) in EtOAc(150 ml) at 0° C. was added saturated aq. NaHCO₃ (150 ml) and thereaction mixture was stirred for 10 min at 0° C. NaBr (1.5 g, 14.4 mmol,0.01 equiv.) was added to the reaction mixture, followed by TEMPO(0.0225 g, 0.144 mmol, 0.1 equiv), and bleach (5.25% in H2O, 20.4 ml,14.4 mmol, 1.0 equiv.). The reaction mixture was stirred for 15 min at0° C. The reaction was monitored by TLC in 1:2 EtOAc/hexane whichindicted presence of starting material. Additional NaOCl (2 ml) wasadded to the reaction mixture and was stirred for 15 min at 0° C. andthen it was quenched with saturated Na₂S₂O₃ (20 ml). The reactionmixture was extracted with EtOAc (1 50 ml×3). The combined organiclayers were dried over (MgSO₄), filtered and concentrated to give crudeCompound 93 (8 g) which was used in the next reaction without furtherpurification.

Step 4:

A mixture of Compound 93 (8 g, 14.1 mmol, 1.0 equiv.) and HMPA (50 ml)was heated at 170° C. for two h. The reaction mixture was cooled to 23°C. and quenched with water (50 ml). The reaction mixture was extractedwith Et₂O (150 ml×3). The combined organic layers were dried over(MgSO₄), filtered and concentrated. The crude product purified by columnchromatography over Biotage (7:3, hexane:EtOAc) to afford Compound 94(3.8 g, 40% over three steps), Electrospray MS [M+1]⁺ 550.1.

Step 5:

Compound 95 was prepared from Compound 94 using the procedure similar tothe preparation of Compound 47 from Compound 45. Electrospray MS [M+1]⁺566.1.

Step 6:

Compound 95 was converted toless polar isomer Example 103a, ElectrosprayMS [M+1]⁺ 502.1, and more polar isomer Example 103b, Electrospray MS[M+1]⁺ 502.1, using the procedure similar to the preparation of Example43a and Example 44b from Compound 47.

Example 104

Step 1:

Compound 96 was prepared from Compound 1 using the procedure similar tothe preparation of Compound 3 from Compound 1. Electrospray MS [M+1]⁺566.1 for the Compound 106.

Step 2:

Compound 96 was converted to a mixture of Example 104a and Example 104busing the procedure similar to the preparation of Examples 43a and 44bfrom Compound 2. The mixture of two isomers was separated on HPLC“ChiralPak AD column” using (5:95, IPA:hexane) to afford pure less polarisomer Example 104a, Electrospray MS [M+1]⁺ 502.1 and more polar isomerExample 104b, Electrospray MS [M+1]⁺ 502.1.

Example 105

Example 105 was prepared from Compound 54 using the procedure similar tothe preparation of Compound 62 from Compound 54, but using CH₃NH₂ (2M inTHF) in place of ammonia (0.5M in 1,4-dioxane). Electrospray MS [M+1]⁺504.1.

Example 106a and Example 106b

Step1:

To a solution of ethyl vinyl ether (2.51 ml, 26.1 mmol) in THF (50 ml)at −78° C. under N₂, t-BuLi (6.6 ml, 11.2 mmol, 1.7M in pentane) wasadded. The mixture was warmed to 0° C. and stirred until the color ofthe solution turned pale yellow. The mixture was then re-cooled at −78°C. and a solution of Compound 47(2.16 g, 3.73 mmol) in THF (20 ml) wasadded. The mixture was stirred at −78° C. for 1 h before quenched withsaturated NaHCO₃ solution. Water and Et₂O were added to the mixture.Layers were separated and the aqueous layer was extracted with Et₂O (200ml×2). The combined organic layers were dried (K₂CO₃, Na₂SO₄) andfiltered. Solvents were removed in vacuum to give an alcohol as yellowoil. The alcohol was dissolved in CH₂Cl₂ (20 ml) and ozone was bubbledthrough the solution at −78° C. until pale blue color persisted. (CH₃)₂S(2.7 ml, 37.3 mmol) was added and the mixture was warmed to RT. Solventswere removed in vacuum and purification by column chromatography[CH₂Cl₂] gave an ester as colorless oil. The ester was dissolved in EtOH(20 ml) and a catalytic amount of Pd(OH)₂ (20% on carbon) was added. Themixture was shaken in a Parr hydrogenator at 45 psi overnight. Themixture was filtered through a pad of Celite and solvents were removedin vacuum to give a colorless oil. Separation by column chromatography[hexane-EtOAc, 4:1(v/v)] gave Compound 97 as colorless oil.

Step 2:

Compound 97 was dissolved in CH₃OH (10 ml) and ammonia was bubbledthrough the solution for 30 min. The mixture was stirred at RT overnightand solvents were removed in vacuum to give a yellow oil. Separation byHPLC using Chiralcel OD [hexane-isopropanol, 9:1 (v/v)] gave the lesspolar major isomer Example 106a (15% overall) as white foam.Electrospray MS [M+1]⁺=491.1. Continuous elution with the same solventsystem gave the more polar minor isomer Example 106b (10% overall) aswhite foam. Electrospray MS [M+1]⁺=491.1.

Example 107

To a solution of cyclopropylamine (17 μl, 0.20 mmol) in toluene (1 ml)at RT under N₂, Al(CH₃)₃(0.1 ml, 0.20 mmol, 2.0M in toluene) was added.The mixture was allowed to stir at RT for 20 min. and a solution ofCompound 97 (20 mg, 0.040 mmol) in toluene (1 ml) was added. The mixturewas heated at 60° C. overnight and was cooled to RT. EtOAc was added andthe mixture was quenched with saturated potassium sodium tartaratesolution. The layers were separated and the aqueous layer was extractedwith EtOAc (100 ml×2). The combined organic layers were dried (MgSO₄)and filtered. Solvents were removed in vacuum and purification by columnchromatography [hexane-EtOAc, 2:1 (v/v)] gave Example 107 (11 mg, 56%)as colorless oil. Electrospray MS [M+1]⁺=531.

Example 108

Example 108a and Example 108b were prepared from Compound 97 using theprocedure similar to the preparation of Example 107 from Compound 97 butusing 2,2,2-trifluoroethylamine in place of cyclopropylamine.Electrospray MS [M+1]⁺ 573.1 for the less polar isomer Example 108a andElectrospray MS [M+1]⁺ 573.1 for the more polar isomer Example 108b.

Example 109

Step 1:

To a solution of diamine Example 13 (150 mg, 0.336 mmol, 1 equiv) inanhydrous THF (5 ml) at 0° C. was added tert-butylcarbazine (44.4 mg,0.336 mmol, 1 equiv) followed by CDI (65.4 mg, 0.404 mmol, 1.2 equiv).The reaction mixture was warmed to RT and stirred for 2 h. The reactionmixture was then concentrated and purified on a biotage (5:95MeOH/EtOAc) to give Compound 98 (170 mg, 84%), Electrospray MS [M+1]⁺605.3.

Step 2:

To a solution of Compound 98 (170 mg, 0.281 mmol, 1 equiv) in anhydrousCH₂Cl₂ (15 ml) at 0° C. was added a 4M HCl solution in 1,4-dioxane (0.7ml, 2.81 mmol, 10 equiv). The reaction mixture was warmed to RT andstirred for 18 h. The reaction mixture was quenched with sat. aq. NaHCO₃(100 ml) and extracted with EtOAc (2×150 ml). The organic layer wasdried (Na₂SO₄), filtered and concentrated. The crude product Compound 99was used in the next reaction without further purification.

Step 3:

To a solution of Compound 99 (160 mg, 0.317 mmol, 1 equiv) in anhydrousDMF (5 ml) was added formaimidine acetate (165 mg, 1.6 mmol, 5 equiv)and the reaction mixture was stirred at RT for 30 min. HOAc (0.091 ml,1.6 mmol, 5 equiv) was added and the reaction mixture was heated at 80°C. for 6 h. The reaction mixture was then cooled to RT, poured intoEtOAc (200 ml) and washed with water (3×100 ml). The organic layer wasdried (Na₂SO₄), filtered and concentrated. The crude mixture waspurified on Gilson (1:9 H₂O/CH₃CN) to give Example 109 (50 mg, 35%),Electrospray MS [M+1]⁺ 515.3.

Example 110a and Example 110b

Step 1:

Using a procedure similar to Example 11, step 2, Compound 47 wasconverted to the corresponding sulfinimine, Compound 100.

Step 2:

Following a procedure similar to Example 11, Step 3, Compound 100 wasconverted to sulfinamide Compounds 101a and 101b.

Step 3:

A 15 ml pear-shaped flask was charged with Compound 101b (140 mg, 0.193mmol, 1 equiv) and CH₂Cl₂ (1 ml). To this pale yellow solution was addedGrubbs' catalyst (13.7 mg, 0.016 mmol, 0.084 equiv), and methyl acrylate(21 μl, 0.232 mmol, 1.2 equiv). The resulting reddish solution washeated at 40° C. overnight and quenched with methylsulfoxide (0.2 ml).After stirring at RT for 20 h, it was diluted with Et₂O and washed withwater. The organic layer was dried over MgSO₄, filtered, andconcentrated. The residue was purified by silica column to give Compound102 (100 mg, 66%).

Step 4:

A RBF was charged with Compound 102 (100 mg, 0.128 mmol, 1 equiv) inEtOH (3 ml), and Pd(OH)₂ on carbon (90 mg, 0.128 mmol, 1 equiv, 20% wt).A hydrogen balloon was attached on the top and the mixture washydrogenated overnight. The reaction mixture was carefully passedthrough a celited funnel and the celite pad was washed thoroughly withMeOH. The filtrate was concentrated, then re-taken up into MeOH (2 ml),treated with HCl (2 ml, 4.0M in 1,4-dioxane), stirred at RT for 2 h,then concentrated again, retaken up again into MeOH (5 ml), treated withan excess amount of K₂CO₃, and heated at 50° C. for 3 h, filtered,concentrated, and the resulted residue was purified on a silica columnto afford Example 110a (42 mg, 64%), Electrospray MS [M+1]⁺ 515.1

Example 110b (49%) was prepared by a similar procedure, but usingCompound 101a. Electrospray MS [M+1]⁺ 515.1

Example 111a and Example 111b

Step 1:

An RBF was charged with a mixture of Compound 101a and 101b (180 mg,0.248 mmol, 1.0 equiv) and CH₂Cl₂ (2 ml). This pale orange solution wascooled to −78° C., and then O₃ was bubbled in. After the solution turnedpale blue, the reaction solution was stirred at −78° C. for 10 min, thenit was -flushed with N₂ to get rid of O₃. The solvent was then removedcarefully. The residue was dissolved in EtOH followed by addition ofNaBH₄ (120 mg). The solution was stirred at RT for 12 h. It was quenchedwith NH₄Cl solution. The reaction was extracted with EtOAc (3×10 ml).The organic solution was washed with brine, dried and concentrated togive Compound 103, which was used in the next reaction without furtherpurification.

The crude Compound 103 was dissolved in MeOH (2 ml) and cooled to 0° C.,followed by the addition of HCl (6 ml, 4N in dioxane). After stirringfor 3 h, the solvent was removed and the residue was redissolved in 3 mlCH₂Cl₂, followed by the addition of DIEA (178 μl). The solution wascooled to 0° C., triphosgene (36 mg) was added, and the reaction wasallowed to warm to RT and stirred for 3 h. It was then diluted withEtOAc, washed with 5% HCl, NaHCO₃ (aq.) and brine. The organic layerswere dried with Na₂SO₄, filtered and concentrated. The crude product washydrogenated to give a mixture of Example 111a and 111b. The mixture wasseparated using prep TLC (5% MeOH in CH₂Cl₂) to give Example 111a (lesspolar) and Example 111b (more polar). Electrospray MS Example 111a[M+1]⁺ 517.1; Example 111a [M+1]⁺ 517.1.

Example 112

To a solution of ethyl propiolate (83 μl, 0.82 mmol) in THF (2 ml) at−78° C. under N₂, t-butyllithium (0.48 ml, 0.82 mmol, 1.7M in pentane)was added. The mixture was stirred at −78° C. for 10 min and a solutionof Compound 47 (158 mg, 0.27 mmol) in THF (1 ml) was added. The mixturewas stirred at −78° C. for 1 h before quenching with HOAC at −78° C.Water and EtOAc were added to the mixture. Layers were separated and theaqueous layer was extracted with EtOAc (200ml×2). The combined organiclayers were dried (MgSO₄) and filtered. Solvents were removed in vacuumand purification by column chromatography.[hexanes-EtOAc, 4:1 (v/v)]gave a colorless oil (112 mg, 61%). The oil was dissolved in EtOH andcatalytic amount of palladium (10% on charcoal) was added. The mixturewas shaken in a Parr hydrogenator at 45 psi overnight. The mixture wasfiltered through a pad of celite and solvents were removed in vacuum togive an ester as a colorless oil. The oil was dissolved in CH₃OH (10 ml)and ammonia was bubbled through the solution for 30 min. The mixture wasstirred at RT overnight and solvents were removed in vacuum.Purification by column chromatography [CH₃OH-EtOAc, 1:9 (v/v)] gaveExample 112 as a colorless oil (54 mg, 61%). Electrospray MS[M+1]⁺=519.1.

Examples 113a and 113b

To a solution of Compound 51 (1.97 g, 3.10 mmol) in CH₂Cl₂ (50 ml) at−78° C., DIBAL-H (9.3 ml, 9.3 mmol, 1.0 M in toluene) was added. Themixture was stirred at −78° C. for 1 h before it was quenched withsaturated potassium sodium tartrate solution. The mixture was warmed toRT and water and EtOAc were added. Layers were separated and the aqueouslayer was extracted with EtOAc (200 ml×2). The combined organic layerswere dried (MgSO₄) and filtered. Solvents were removed in vacuum andcolumn chromatography [hexane-EtOAc, 3:1(v/v)] gave the allylic alcohol(1.6 g, 85%) as colorless oil.

The allylic alcohol (1.6 g, 2.63 mmol) was dissolved intriethylorthoacetate (30 ml) and catalytic amount of propanoic acid wasadded. The mixture was heated in a sealed-tube at 130° C. overnight.Solvents were removed in vacuum and column chromatography [hexane-Et₂O,5:1 (v/v)] gave the alkene (891 mg, 50%) as colorless oil.

The alkene (891 mg, 1.31 mmol) was dissolved in CH₂Cl₂ (20 ml) and wascooled at −78° C. O₃ was bubbled through the solution until a pale bluecolor persisted in the solution. The mixture was purged with N₂ until acolorless solution was obtained. Methyl sulfide (1 ml) was added and themixture was warmed to RT. Solvents were removed in vacuum and columnchromatography [Hexanes-EtOAc, 5:1(v/v)] gave the aldehyde (800 mg, 90%)as colorless oil.

The aldehyde (280 mg, 0.41 mmol) was dissolved in isoprene (2.4 ml) andt-butyl alcohol (7 ml) at RT. A solution of sodium chlorite (414 mg,4.12 mmol) in sodium dihydrogenphosphate (4 ml, 20% wt. in water) wasadded. The mixture was stirred at RT vigorously for 2 h. Water and EtOAcwere added. Layers were separated and the aqueous layer was extractedwith EtOAc (250 ml×2). The combined organic layers were dried (MgSO₄)and filtered. Solvents were removed in vacuum to give a crude acid asyellow oil.

The crude acid was dissolved in CH₂Cl₂ (10 ml) at RT anddiisopropylamine (0.22 ml, 1.24 mmol), followed by PyBOP (322 mg, 0.62mmol) were added. The mixture was stirred at RT for 20 min. before asolution of ammonia in dioxane (8 ml, 4.12 mmol) was added. The mixturewas stirred at RT overnight before it was quenched with saturated NaHCO₃solution. Water and EtOAc were added. Layers were separated and theaqueous layer was extracted with EtOAc (250 ml×2). The combined organiclayers were dried (MgSO₄) and filtered. Solvents were removed in vacuumto give the crude amide as yellow oil.

The crude amide was dissolved in CH₃OH (10 ml) and Pd(OH)₂ (20% oncarbon) was added. The mixture was stirred under H₂ (balloon) for 4 h.Solid was filtered through a pad of celite and solvents were removed invacuum to give the crude amino-amide as yellow oil.

The crude amino-amide was dissolved in CH₃OH and excess NaOCH₃ wasadded. The mixture was heated at 60° C. for 1 h before it was quenchedwith saturated with saturated NH₄Cl solution. Water and EtOAc wereadded. Layers were separated and the aqueous layer was extracted withEtOAc (250 ml×2). The combined organic layers were dried (MgSO₄) andfiltered. Solvents were removed in vacuum and column chromatography[hexane-EtOAc, 2:1 (v/v)] gave the less polar isomer Example 113a (20mg, 9%, 4 steps overall) as white foam. Electrospray MS [M+1]⁺=515.1.Continuous elution with the same solvent system gave the more polarisomer Example 113b (25 mg, 12%, 4 steps overall) as colorless oil.

Electrospray MS [M+1]⁺=515.1.

The above description is not intended to detail all modifications andvariations of the invention. It will be appreciated by those skilled inthe art that changes can be made to the embodiments described abovewithout departing from the inventive concept. It is understood,therefore, that the invention is not limited to the particularembodiments described above, but is intended to cover modifications thatare within the spirit and scope of the invention, as defined by thelanguage of the following claims.

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein Ar¹ is phenyl,wherein said phenyl can be unsubstituted or substituted with 1 to 3fluoro; Ar² is bis(trifluoromethyl)phenyl; X¹ is —O—; R¹ and R² areindependently selected from the group consisting of H, C₁-C₆ alkyl orhydroxyl (C₁-C₃alkyl), providing that at least one of R¹ and R² is H; R³is H; R⁶ and R⁷ are each H; n₂ is 2; R⁴ and R⁵ are each independentlyselected from the group consisting of —(CR²⁸R²⁹)_(n1)-G, where, n₁ is0-5; and G is H, —NR¹³R¹⁴, —NR¹²C(O)R¹⁴, —C(O)NR¹³R¹⁴, —OC(O)NR¹³R¹⁴,NR¹²C(O)OR¹³, —NR¹²(C(O)NR¹³R¹⁴), —NR¹²S)₂R¹³, R¹⁹-heteroaryl, R¹⁹-aryl,wherein heteroaryl is selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl, thienyl,benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazoyl,tetrazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl,pyrrolyl, isoxazolyl, 1,3,5-triazinyl or indolyl and aryl is selectedfrom phenyl, —OH, —O(C₁-C₆alkyl), —C(OR¹²)(R¹³)(R¹⁴), —OC(O)R¹⁴,——C(O)R¹³, heterocycloalkenyl optionally substituted by 1 substituentindependently selected from the group consisting of R³⁰ and R³¹,

provided that R⁴ and R⁵ are not both selected from the group consistingof H, alkyl and cycloalkyl; further provided that, when one of R⁴ and R⁵is —OH, then the other one of R⁴ and R⁵ is not alkyl or (R¹⁹aryl); R¹²is H, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R¹³ and R¹⁴ are reachindependently selected from the group consisting of H, C₁-C₆alkyl,—CH₂CF₃, C₃-C₆ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, phenyl orpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl,thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,triazoyl, tetrazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl,oxazolyl, pyrrolyl, isoxazolyl, 1,3,5-triazinyl or indolyl; or R¹³ andR¹⁴, together with the nitrogen atom to which they are both attached,form a 5- to 6-membered saturated or unsaturated ring that is optionallysubstituted with —OR¹², where one of the carbon atoms in the ring isoptionally replaced by a heteroatom selected from —O—; n₆ is 0, 1 or 2;R¹⁸ is H; each R¹⁹ is a substituent on the aryl or heteroaryl ring towhich it is attached and is independently selected from the groupconsisting of H or C₁-C₆ alkyl; R²³ and R²⁴ are each independentlyselected from the group consisting of H and C₁-C₆ alkyl; or R²³ and R²⁴,together with the carbon atom to which they are both attached, form aC═O or cyclopropyl group; R²⁷ is H, —OH or C₁-C₆ alkyl; R²⁸ and R²⁹ areeach independently selected from the group consisting of H andC₁-C₂alkyl; R³⁰ and R³¹ are each independently selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl and —C(0)NR¹³R¹⁴; or R³⁰ and R³¹, togetherwith the carbon atom to which they are both attached, form ═O, ═S, acyclopropyl ring or ═NR³⁶; R³² and R³³ are each H; R³⁴ is H, C₁-C₆alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl orhydroxyl(C₂-C₆)alkyl; R³⁵ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, -P(0)(OH)₂, allyl, hydroxyl(C₂-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, —SO₂R¹⁵ or —(CH₂)₂—N(R¹²)—SO₂—R¹⁵; R³⁶ is H,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, —NO₂, —CNor OR¹²; R³⁷ is 1 to 3 substituents independently selected from thegroup consisting of H, C₁-C₆ alkyl, —OH, C₁-C₆ alkoxy and halogen; r is1to 3; X² is —NR³⁵—, —O—, —S—, —S(O)—, —S(O₂—, —CH₂—, —CF₂— or —CR¹²F—;X³ is —NR³⁴—, —N(CONR¹³R¹⁴)—, —N(CO₂R¹⁵)—, —N(COR¹²)—, —N(SO₂NHR¹³)—,—O—, —S—, —S(O)—, SO₂—, —CH₂—, —CF₂—, or CR¹²F—; n₃ is 1 to 5; and n₅ is1 to 3; or a diastereomer, enantiomer, stereoisomer, regiostereomer,rotomer, or tautomer thereof.
 2. The compound or salt according to claim1 wherein R⁴ is —NR¹³R¹⁴, —NR¹²C(O)R¹⁴, NR¹²C(O)OR¹³, NR¹²(C(O)NR¹³R¹⁴,—OH, —O—(C₁-C₆)alkyl, —O—(C₃-C₈cycloalkyl, —OC(O)R¹⁴, —OC(O)NR¹³R¹⁴, —NR—SO₂NR¹³R¹⁴, R¹⁹-heteroaryl,

wherein X₂ is —O—, —S—, —CH₂— or —NR³⁵; and R⁵ is —C(O)OR¹³ or—C(O)NR¹³R¹⁴.
 3. The compound or salt according to claim 2 where R12 andR27 are independently selected from the group consisting of H and —CH3;n3 is 2 or 3; and n5 is 1 or
 2. 4. the compound or salt according toclaim 2, wherein R12 and R27 are H; n3 is 2 or 3; and n5 is 1 or
 2. 5. Acompound having the following structure:

and pharmaceutically acceptable salts thereof.
 6. A compound having thefollowing structure:

and pharmaceutically acceptable salts thereof.
 7. A compound having thefollowing structure:

and pharmaceutically acceptable salts thereof.
 8. The compound or saltaccording to claim 1, wherein the compound is:


9. A pharmaceutical composition comprising a therapeutically effectiveamount of at least one compound of claim 1 in a pharmaceuticallyacceptable carrier.
 10. The pharmaceutical composition according toclaim 9, further comprising at least one serotonin reuptake inhibitor.11. The pharmaceutical composition according to claim 9, furthercomprising at least one serotonin 5-HT3 receptor antagonist, or at leastone corticosteroid or at least one substituted benzamide.
 12. Thepharmaceutical composition according to claim 9, further comprising atleast one serotonin 5-HT3 receptor antagonist and at least one corticoidsteroid.
 13. The pharmaceutical composition according to claim 9,further comprising at least one substituted benzamide and at least onecorticosteroid.
 14. The pharmaceutical composition according to claim10, where the selective serotonin reuptake inhibitor is fluoxetine,fluvoxamine, paroxetine, sertraline, or a pharmaceuticall acceptablesalt thereof.
 15. The pharmaceutical composition according to claim 11,where the serotonin 5-HT3 receptor antagonist is ondansetron,dolasetron, palonsetron or granisetron, the corticosteroid isdexamethasone, and the substituted benzamide is metoclopramide.
 16. Thepharmaceutical composition according to claim 12 where the serotonin5-HT3 receptor antagonist is ondansetron, dolasetron, palosetron orgranisetron, the corticosteroid is dexamethasone.
 17. The pharmaceuticalcomposition according to claim 11, wherein the corticosteroid isdexamethasone, and the substituted benzamide is metoclopramide.
 18. Thepharmaceutical composition according to claim 13, where thecorticosteroid is dexamethasone and the substituted benzamide ismetoclopramide.
 19. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.